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  • 1.
    Abrahamsson, B.
    et al.
    AstraZeneca R&D, S-43183 Molndal, Sweden..
    McAllister, M.
    Pfizer, Tadworth, Surrey, England..
    Augustijns, P.
    Katholieke Univ Leuven, Leuven, Belgium..
    Zane, P.
    Sanofi Aventis, Paris, France..
    Butler, J.
    GSK, Brentford, England..
    Holm, R.
    Johnson & Johnson, Machelen, Belgium..
    Langguth, P.
    Johannes Gutenberg Univ Mainz, Mainz, Germany..
    Lindahl, A.
    Med Prod Agcy, Uppsala, Sweden..
    Muellertz, A.
    Univ Copenhagen, Copenhagen, Denmark..
    Pepin, X.
    United Kingdom, AstraZeneca R&D, Cambridge, England..
    Rostami-Hodjegan, A.
    Certara, London, England.;Univ Manchester, Manchester, Lancs, England..
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Berntsson, M.
    AstraZeneca R&D, S-43183 Molndal, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project2020In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 152, p. 236-247Article in journal (Refereed)
    Abstract [en]

    OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.

  • 2.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Al-Tikriti, Yassir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Single bead investigation of a clinical drug delivery system – a novel release mechanism2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 292, p. 235-247Article in journal (Refereed)
    Abstract [en]

    Microgels, such as polymeric hydrogels, are currently used as drug delivery devices (DDSs) for chemotherapeutics and/or unstable drugs. The clinical DDS DC bead® was studied with respect to loading and release, measured as relative bead-volume, of six amphiphilic molecules in a micropipette-assisted microscopy method. Theoretical models for loading and release was used to increase the mechanistic understanding of the DDS.

    It was shown that equilibrium loading was independent of amphiphile concentration. The loading model showed that the rate-determining step was diffusion of the molecule from the bulk to the bead surface (‘film control’). Calculations with the developed and applied release model on the release kinetics were consistent with the observations, as the amphiphiles distribute unevenly in the bead. The rate determining step of the release was the diffusion of the amphiphile molecule through the developed amphiphile-free depletion layer. The release rate is determined by the diffusivity and the tendency for aggregation of the amphiphile where a weak tendency for aggregation (i.e. a large cacb) lead to faster release. Salt was necessary for the release to happen, but at physiological concentrations the entry of salt was not rate-determining. This study provides valuable insights into the loading to and release from the DDS. Also, a novel release mechanism of the clinically used DDS is suggested.

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  • 3.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Degerstedt, Oliver
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lilienberg, Elsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lipiodol-based emulsions used for transarterial chemoembolization and drug delivery: Effects of composition on stability and product quality2019In: Journal of Drug Delivery Science and Technology, ISSN 1773-2247, Vol. 53, article id UNSP 101143Article in journal (Refereed)
    Abstract [en]

    Transarterial chemoembolization with emulsion-based formulations using doxorubicin hydrochloride (DOX) and Lipiodol (R) is the golden standard for the loco-regional treatment of unresectable hepatocellular carcinoma (HCC). However, from a pharmaceutical quality perspective these emulsions are poorly characterized. In this study, clinically relevant Lipiodol (R)-based emulsions were characterized in terms of emulsion stability, continuous phase classification and droplet-size distribution. Also, the solubility of DOX in the different emulsion components and the distribution of DOX to the lipid phase were investigated. These are key features to investigate due to the claimed tumor-seeking properties of Lipiodol (R). The in vitro release of DOX was studied in a miniaturized dialysis method and an empirical release model was applied to adjust for the passage of DOX across the dialysis membrane. The most stable emulsion ( > 72 h) was classified as water-in-oil (w/o), had the highest distribution of DOX to the lipid phase (20%) and an aqueous-to-lipid phase ratio of 1:4. The composition of the aqueous phase was a mixture (v/v) of iohexol (85%) and water (15%). Emulsions containing iohexol and a high aqueousto-lipid phase ratio (1:2-1:4) displayed prolonged in vitro release profiles of DOX. This study further emphasizes the medical need to standardize these emulsion-based drug delivery systems.

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  • 4.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Axén, N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A miniaturized in vitro release method for investigating drug-release mechanisms2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 486, no 1-2, p. 339-349Article in journal (Refereed)
    Abstract [en]

    We have evaluated a miniaturized in vitro method, based on the mDISS Profiler (TM) technique that enables on-line monitoring of drug release from a 21 mu l sample with 10 ml of release medium. Four model drugs in eight clinically used formulations, including both solid and non-solid drug delivery systems, were investigated. The acquired data were compared with historical in vitro release data from the same formulations. Use of the Weibull function to describe the in vitro drug-release profiles allowed discrimination between the selected formulations with respect to the drug-release mechanisms. Comparison of the release data from the same formulation in different in vitro set-ups showed that the methodology used can affect the mechanism of in vitro release. We also evaluated the ability of the in vitro methods to predict in vivo activity by comparing simulated plasma concentration-time profiles acquired from the application of the biopharmaceutical software GI-Sim to the in vitro observations. In summary, the simulations based on the miniaturized-method release data predicted the plasma profiles as well as or more accurately than simulations based on the historical release data in 71% of the cases and this miniaturized in vitro method appears to be applicable for both solid and non-solid formulations.

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  • 5.
    Ahnfelt, Emelie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hansson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vitro Release Mechanisms of Doxorubicin From a Clinical Bead Drug-Delivery System2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 11, p. 3387-3398Article in journal (Refereed)
    Abstract [en]

    The release rate of doxorubicin (DOX) from the drug-delivery system (DDS), DC Bead, was studied by 2 miniaturized in vitro methods: free-flowing and sample reservoir. The dependencies of the release mechanisms on in vitro system conditions were investigated experimentally and by theoretical modeling. An inverse relationship was found between release rates and bead size, most likely due to the greater total surface area. The release rates correlated positively with temperature, release medium volume, and buffer strength, although the release medium volume had larger effect than the buffer strength. The sample reservoir method generated slower release rates, which described the in vivo release profile more accurately than the free-flowing method. There was no difference between a pH of 6.3 or 7.4 on the release rate, implying that the slightly acidic tumor microenvironment is less importance for drug release. A positive correlation between stirring rate and release rate for all DDS sizes was observed, which suggests film controlled release. Theoretical modeling highlighted the influence of local equilibrium of protonation, self-aggregation, and bead material interactions of DOX. The theoretical release model might describe the observed larger sensitivity of the release rate to the volume of the release medium compared to buffer strength. A combination of miniaturized in vitro methods and theoretical modeling are useful to identify the important parameters and processes for DOX release from a micro gel-based DDS.

  • 6. Amidon, K. S.
    et al.
    Langguth, P.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Yu, L.
    Amidon, G. L.
    Bioequivalence of Oral Products and the Biopharmaceutics Classification System: Science, Regulation, and Public Policy2011In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 90, no 3, p. 467-470Article in journal (Refereed)
    Abstract [en]

    The demonstration of bioequivalence (BE) is an essential requirement for ensuring that patients receive a product that performs as indicated by the label. The BE standard for a particular product is set by its innovator, and this standard must subsequently be matched by generic drug products. The Biopharmaceutics Classification System (BCS) sets a scientific basis for an improved BE standard for immediate-release solid oral dosage forms. In this paper, we discuss BE and the BCS, as well as the issues that are currently relevant to BE as a pharmaceutical product standard.

  • 7.
    Arvidsson, Björn
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Allard, Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöberg, Per Johan Ragnar
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Physical and Analytical Chemistry.
    Online capillary solid phase extraction and liquid chromatographic separation with quantitative tandem mass spectrometric detection (SPE-LC-MS/MS) of ximelagatran and its metabolites in a complex matrix.2009In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 877, no 3, p. 291-297Article in journal (Refereed)
    Abstract [en]

    This work presents the development and validation of a fully automated quantitative analysis method of melagatran, its prodrug ximelagatran, and its major metabolites for the study of drug behavior in biofluids. The method involves online sample clean-up and enrichment on a C4 capillary column followed by separation on a capillary C18 column. Electrospray ionization tandem mass spectrometric detection in positive ion mode was performed with multiple reactions monitoring of eight different transients, divided into two time segments with four transients each. The structural similarity, the complexity of the matrix (pig liver extract) and the formation of isobaric fragment ions, made efficient chromatographic separation necessary. The analysis method provides valid accuracy (<9%; RSD%), precision (<8%; RSD%), linearity (<1.2 nM–1 μM; R2 > 0.999), limit of quantitation (<3.6 nM), retention repeatability (<1.2%; RSD%), selectivity, as well as analyte and column stabilities over a wide concentration range.

  • 8.
    Augustijns, Patrick
    et al.
    Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Drug Delivery & Disposit, Herestr 49,Box 921, B-3000 Leuven, Belgium..
    Vertzoni, Maria
    Natl & Kapodistrian Univ Athens, Sch Hlth Sci, Dept Pharm, Athens, Greece..
    Reppas, Christos
    Natl & Kapodistrian Univ Athens, Sch Hlth Sci, Dept Pharm, Athens, Greece..
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Inst Pharmaceut & Biomed Sci, D-55131 Mainz, Germany..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Abrahamsson, Bertil
    AstraZeneca Gothenburg, Operat, Oral Prod Dev Pharmaceut Technol & Dev, S-43183 Molndal, Sweden..
    Hasler, William L.
    Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA..
    Baker, Jason R.
    Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA..
    Vanuytsel, Tim
    Katholieke Univ Leuven, Translat Res Ctr Gastrointestinal Disorders TARGI, Leuven, Belgium..
    Tack, Jan
    Katholieke Univ Leuven, Translat Res Ctr Gastrointestinal Disorders TARGI, Leuven, Belgium..
    Corsetti, Maura
    Nottingham Univ Hosp NHS Trust, NIHR Nottingham Biomed Res Ctr BRC, Nottingham, England.;Univ Nottingham, Nottingham, England.;Univ Nottingham, Nottingham Digest Dis Ctr, Sch Med, Nottingham, England..
    Bermejo, Marival
    Miguel Hernandez Univ, Dept Engn Pharm Sect, Alicante 03550, Spain..
    Paixao, Paulo
    Univ Lisbon, Fac Pharm, Res Inst Med iMed ULisboa, Av Prof Gama Pinto, P-1649003 Lisbon, Portugal..
    Amidon, Gordon L.
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA..
    Hens, Bart
    Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Drug Delivery & Disposit, Herestr 49,Box 921, B-3000 Leuven, Belgium..
    Unraveling the behavior of oral drug products inside the human gastrointestinal tract using the aspiration technique: History, methodology and applications2020In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 155, article id 105517Article in journal (Refereed)
    Abstract [en]

    Fluid sampling from the gastrointestinal (GI) tract has been applied as a valuable tool to gain more insight into the fluids present in the human GI tract and to explore the dynamic interplay of drug release, dissolution, precipitation and absorption after drug product administration to healthy subjects. In the last twenty years, collaborative initiatives have led to a plethora of clinical aspiration studies that aimed to unravel the luminal drug behavior of an orally administered drug product. The obtained drug concentration-time profiles from different segments in the GI tract were a valuable source of information to optimize and/or validate predictive in vitro and in silico tools, frequently applied in the non-clinical stage of drug product development. Sampling techniques are presently not only being considered as a stand-alone technique but are also used in combination with other in vivo techniques (e.g., gastric motility recording, magnetic resonance imaging (MRI)). By doing so, various physiological variables can be mapped simultaneously and evaluated for their impact on luminal drug and formulation behavior. This comprehensive review aims to describe the history, challenges and opportunities of the aspiration technique with a specific focus on how this technique can unravel the luminal behavior of drug products inside the human GI tract by providing a summary of studies performed over the last 20 years. A section `Best practices' on how to perform the studies and how to treat the aspirated samples is described. In the conclusion, we focus on future perspectives concerning this technique.

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  • 9.
    Ayoun Alsoud, Rami
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Le Moan, Natacha
    Holten-Andersen, Lars
    Knudsen, Tom
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Simonsson, Ulrika S. H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Model-based interspecies scaling for predicting human pharmacokinetics of CB 4332, a complement factor I proteinManuscript (preprint) (Other academic)
    Abstract [en]

    The extrapolation of a protein pharmacokinetics (PK) from preclinical to clinical studies can be less reliable than for small molecules. CB 4332 is a 150 kDa recombinant complement factor I (CFI) protein. In order to support clinical development, interspecies scaling of CB 4332 using traditional and model-based approaches was performed to inform first-in-human (FIH) dose selection. Plasma concentration versus time data from four preclinical PK studies of single intravenous (i.v.) and subcutaneous (s.c.) CB 4332 dosing in mice, rats and nonhuman primates (NHPs) were modeled simultaneously using naive pooling including allometric scaling. The human-equivalent dose was calculated using the preclinical no observed adverse effect level (NOAEL) as part of the dose-by-factor approach. Pharmacokinetic modelling of CB 4332 revealed species-specific differences in the elimination, which was accounted for by including an additional rat-specific clearance. Signs of anti-drug antibodies (ADA) formation in all rats and some NHPs were observed. Consequently, an additional ADA-induced clearance parameter was estimated including the time of onset. Using the traditional dose-by-factor approach, a maximum recommended starting s.c. dose of 0.9 mg/kg once weekly was calculated using the NOAEL observed in NHPs. The model-based clinical trial simulations predicted it to result in a trough concentration at steady state 12.8% of the determined efficacy target for CB 4332 in humans. Interspecies scaling was performed for CB 4332 using traditional and model-based scaling, where PK modeling allowed the inclusion of preclinical PK information from three species, accounted for potential effects of ADA and species differences in elimination, and allowed the prediction of human PK for FIH dose selection.

  • 10.
    Balgoma, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Kullenberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Calitz, Carlemi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Kopsida, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Heindryckx, Femke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Anthracyclins Increase PUFAs: Potential Implications in ER Stress and Cell Death2021In: Cells, E-ISSN 2073-4409, Vol. 10, no 5, article id 1163Article in journal (Refereed)
    Abstract [en]

    Metabolic and personalized interventions in cancer treatment require a better understanding of the relationship between the induction of cell death and metabolism. Consequently, we treated three primary liver cancer cell lines with two anthracyclins (doxorubicin and idarubin) and studied the changes in the lipidome. We found that both anthracyclins in the three cell lines increased the levels of polyunsaturated fatty acids (PUFAs) and alkylacylglycerophosphoethanolamines (etherPEs) with PUFAs. As PUFAs and alkylacylglycerophospholipids with PUFAs are fundamental in lipid peroxidation during ferroptotic cell death, our results suggest supplementation with PUFAs and/or etherPEs with PUFAs as a potential general adjuvant of anthracyclins. In contrast, neither the markers of de novo lipogenesis nor cholesterol lipids presented the same trend in all cell lines and treatments. In agreement with previous research, this suggests that modulation of the metabolism of cholesterol could be considered a specific adjuvant of anthracyclins depending on the type of tumor and the individual. Finally, in agreement with previous research, we found a relationship across the different cell types between: (i) the change in endoplasmic reticulum (ER) stress, and (ii) the imbalance between PUFAs and cholesterol and saturated lipids. In the light of previous research, this imbalance partially explains the sensitivity to anthracyclins of the different cells. In conclusion, our results suggest that the modulation of different lipid metabolic pathways may be considered for generalized and personalized metabochemotherapies.

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  • 11.
    Balgoma, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Univ Valladolid, Inst Biol & Genet Mol IBGM, Unidad Excelencia, Consejo Super Invest Cient CSIC, Valladolid 47003, Spain..
    Kullenberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Peters, Karsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Dahlgren, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Heindryckx, Femke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lennernas, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Orthogonality in Principal Component Analysis Allows the Discovery of Lipids in the Jejunum That Are Independent of Ad Libitum Feeding2022In: Metabolites, ISSN 2218-1989, E-ISSN 2218-1989, Vol. 12, no 9, article id 866Article in journal (Refereed)
    Abstract [en]

    Ad libitum feeding of experimental animals is preferred because of medical relevance together with technical and practical considerations. In addition, ethical committees may require ad libitum feeding. However, feeding affects the metabolism so ad libitum feeding may mask the effects of drugs on tissues directly involved in the digestion process (e.g., jejunum and liver). Despite this effect, principal component analysis has the potential of identifying metabolic traits that are statistically independent (orthogonal) to ad libitum feeding. Consequently, we used principal component analysis to discover the metabolic effects of doxorubicin independent of ad libitum feeding. First, we analyzed the lipidome of the jejunum and the liver of rats treated with vehicle or doxorubicin. Subsequently, we performed principal component analysis. We could identify a principal component associated to the hydrolysis of lipids during digestion and a group of lipids that were orthogonal. These lipids in the jejunum increased with the treatment time and presented a polyunsaturated fatty acid as common structural trait. This characteristic suggests that doxorubicin increases polyunsaturated fatty acids. This behavior agrees with our previous in vitro results and suggests that doxorubicin sensitized the jejunum to ferroptosis, which may partially explain the toxicity of doxorubicin in the intestines.

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  • 12. Benet, Leslie Z.
    et al.
    Amidon, Gordon L.
    Barends, Dirk M.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Polli, James E.
    Shah, Vinod P.
    Stavchansky, Salomon A.
    Yu, Lawrence X.
    The use of BDDCS in classifying the permeability of marketed drugs2008In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 25, no 3, p. 483-488Article in journal (Refereed)
    Abstract [en]

    We recommend that regulatory agencies add the extent of drug metabolism (i.e., >or=90% metabolized) as an alternate method in defining Class 1 marketed drugs suitable for a waiver of in vivo studies of bioequivalence. That is, >or=90% metabolized is an additional methodology that may be substituted for >or=90% absorbed. We propose that the following criteria be used to define>or=90% metabolized for marketed drugs: Following a single oral dose to humans, administered at the highest dose strength, mass balance of the Phase 1 oxidative and Phase 2 conjugative drug metabolites in the urine and feces, measured either as unlabeled, radioactive labeled or nonradioactive labeled substances, account for >or=90% of the drug dosed. This is the strictest definition for a waiver based on metabolism. For an orally administered drug to be >or=90% metabolized by Phase 1 oxidative and Phase 2 conjugative processes, it is obvious that the drug must be absorbed. This proposal, which strictly conforms to the present>or=90% criteria, is a suggested modification to facilitate a number of marketed drugs being appropriately assigned to Class 1.

  • 13.
    Berggren, Sofia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gall, Christine
    Wollnitz, Nadine
    Ekelund, Mats
    Karlbom, Urban
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hoogstraate, Janet
    Schrenk, Dieter
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gene and protein expression of P-glycoprotein, MRP1, MRP2 and CYP3A4 in the small and large human intestine2007In: Molecular Pharmaceutics, ISSN 1543-8384, Vol. 4, no 2, p. 252-257Article in journal (Refereed)
    Abstract [en]

    The cytochrome P450 3A4 enzyme and the ABC-transporters may affect the first-pass extraction and bioavailability of drugs and metabolites. Conflicting reports can be found in the literature on the expression levels of efflux transporters in human intestine and how they vary along the intestine. The relative levels of mRNA and protein of CYP3A4 and the ABC tranporters Pgp (ABCB1), MRP1 (ABCC1), and MRP2 (ABCC2) were determined using RT-PCR and Western blot for human intestinal tissues (n = 14) from jejunum, ileum and colon. The expression of mRNA for CYP3A4, Pgp, and MRP2 was highest in jejunum and decreased toward more distal regions, whereas MRP1 was equally distributed in all intestinal regions. For CYP3A4, a more significant correlation could be established between mRNA and protein expression than for the ABC transporters. The samples showed considerable interindividual variability, especially at the protein level. The apically located Pgp and MRP2 showed a similar expression pattern along the human intestine as for CYP3A4. The gene expression of MRP1 exhibited a more uniform distribution.

  • 14.
    Berggren, Sofia
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Hoogstraate, Janet
    Fagerholm, Urban
    Lennernäs, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Characterization of jejunal absorption and apical efflux of ropivacaine, lidocaine and bupivacaine in the rat using in situ and in vitro absorption models.2004In: Eur J Pharm Sci, ISSN 0928-0987, Vol. 21, no 4, p. 553-60Article in journal (Other scientific)
  • 15.
    Bergman, Ebba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Forsell, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Persson, Eva M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Dickinson, Paul
    Smith, Robert
    Swaisland, Helen
    Farmer, Matthew R.
    Cantarini, Mireille V.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pharmacokinetics of gefitinib in humans: the influence of gastrointestinal factors2007In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 341, no 1-2, p. 134-142Article in journal (Refereed)
    Abstract [en]

    Purpose

    To investigate whether differences in plasma pharmacokinetic profiles of gefitinib between healthy subjects having normal (N; t1/2 > 20 h) and altered (A; t1/2 < 20 h) pharmacokinetic (PK) profiles might be explained by inter-individual variability in gastric emptying and/or precipitation/dissolution of gefitinib in the proximal small intestine.

    Methods

    One hundred healthy male subjects were screened to enable identification of subjects with the two PK profiles. Twenty five subjects from the screening were subsequently enrolled in an intubation study where a 250 mg gefitinib dispersion preparation (IRESSA®, AstraZeneca) was administered directly into the stomach. Intestinal fluid samples were withdrawn continuously for 180 min post-dose using the Loc-I-Gut catheter positioned in the jejunum. The crystalline form of gefitinib was determined using Raman microscopy.

    Results

    There were no differences between normal and altered subjects with regard to gastric emptying or the precipitation/dissolution of gefitinib in jejunal fluid. Due to difficulties in crystalline identification in the jejunal fluid samples, only the same crystalline form as the dosed form was identified.

    Conclusions

    There was no pronounced difference in gastric emptying, precipitation and re-dissolution of gefitinib in proximal human jejunum between normal and altered subjects. Other mechanism(s) are also likely to be important in explaining the inter-individual differences in plasma exposure to gefitinib, such as polymorphism in various metabolic enzymes and/or transport proteins. However, the difference between altered and normal subjects cannot be easily explained and it is likely a multifactorial explanation including low jejunal pH, increased expression of enzymatic and transporter activity and rapid small intestine transit.

  • 16.
    Bergman, Ebba
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Forsell, Patrik
    Faculty of Medicine, Department of Surgical Sciences.
    Tevell, Annica
    Department of Medicinal Chemistry.
    Persson, Eva M
    Hedeland, Mikael
    Department of Medicinal Chemistry.
    Bondesson, Ulf
    Department of Medicinal Chemistry.
    Knutson, Lars
    Faculty of Medicine, Department of Surgical Sciences.
    Lennernäs, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Biliary secretion of rosuvastatin and bile acids in humans during the absorption phase.2006In: Eur J Pharm Sci, ISSN 0928-0987, Vol. 29, no 3-4, p. 205-14Article in journal (Refereed)
  • 17.
    Bergman, Ebba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The Effect of Acute Administration of Rifampicin and Imatinib on the Enterohepatic Transport of Rosuvastatin In Vivo2010In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 40, no 8, p. 558-568Article in journal (Refereed)
    Abstract [en]

    Hepatobiliary transporters efficiently shunt rosuvastatin from the blood stream, into the hepatocyte, followed by transporter-mediated excretion into the bile ducts. This study aimed at investigating the contribution of sinusoidal versus canalicular transport on the pharmacokinetics of an intrajejunal dose of 80mg rosuvastatin in pigs (control group, n=2+6). The transport inhibitors, rifampicin (20mg/kg, n6) and imatinib (14mg/kg, n6), were administered as 2-h long intravenous infusions. Plasma samples were withdrawn from the portal and hepatic vein simultaneously during 5h along with bile sample collection. Rifampicin reduced the hepatic extraction of rosuvastatin by 35% and the area under the curve in the hepatic vein compartment increased by a factor of 6.3 (95% confidence intervals (CI): 3.132, P value <0.01). The increase in the portal vein compartment was less pronounced than in the hepatic vein, 2.0-fold (95% CI: 1.13.8, P value <0.05), suggesting that the inhibition was predominantly located in the liver rather than in the intestine and suggesting inhibition if sinusoidal transport. In contrast, no effect on the pharmacokinetics of rosuvastatin was observed following concomitant administration with imatinib possibly due to insufficient concentration of the inhibitor inside the hepatocyte. Rifampicin significantly affected the hepatobiliary transport of rosuvastatin, however imatinib did not alter the plasma exposure of rosuvastatin.

  • 18.
    Bergman, Ebba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundahl, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fridblom, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The Enterohepatic Disposition of Rosuvastatin in Pigs and The Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil2009In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 12, p. 2349-2358Article in journal (Refereed)
    Abstract [en]

    The hepatobiliary transport and local disposition of rosuvastatin in pig was investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. 80 mg rosuvastatin was administered as an intrajejunal bolus dose in Treatments I, II and III (TI, TII, and TIII, respectively; n=6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a two hour intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In Treatment IV (TIV, n=4) was 5.9 mg rosuvastatin administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH) and femoral veins and bile from the common hepatic duct. The biliary recovery of the administered rosuvastatin dose was 9.0±3.5% and 35.7±15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as the median AUCbile/AUCVH ratio was 1770 (1640-11300) in TI. Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC50-values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI; 0.89±0.06, TII; 0.46±0.13) and increased the AUCVP and AUCVH by 1.6 and 9.1-fold, respectively. In addition, the biliary exposure and fe, bile were reduced by ≈50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the OATP-family, rather than canalicular transporters.

  • 19.
    Bergman, Ebba
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Elin M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Knutson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of a Single Gemfibrozil Dose on the Pharmacokinetics of Rosuvastatin in Bile and Plasma in Healthy Volunteers2010In: Journal of clinical pharmacology, ISSN 0091-2700, E-ISSN 1552-4604, Vol. 50, no 9, p. 1039-1049Article in journal (Refereed)
    Abstract [en]

    The effect of a single intrajejunal dose of gemfibrozil (600 mg) on the plasma pharmacokinetics and biliary excretion of a single intrajejunal dose of rosuvastatin (20 mg) was investigated by using a multichannel catheter positioned in the distal duodenum/proximal jejunum in eight healthy volunteers. Bile and plasma samples were collected every 20 min for 200 min, with additional plasma samples being withdrawn for up to 48 hrs. Gemfibrozil did not affect the bioavailability of rosuvastatin, although it increased the apparent absorption phase during the initial 200 minutes (AUC0-200) by 1.56-fold (95%CI: 1.14-2.15). The interaction was less pronounced in this single dose study than in a previous report when gemfibrozil was administered repeatedly, nevertheless, the interaction coincided with the highest exposure to gemfibrozil. The plausible reason why the interaction in this investigation was only minor is the low exposure to gemfibrozil (and its metabolites), suggesting that the total plasma concentration of gemfibrozil needs to be above 20 µM in order to affect the disposition of rosuvastatin. This study demonstrates the value of monitoring the plasma pharmacokinetics of the inhibitor, and not only the drug under investigation, to improve the mechanistic interpretation.

  • 20. Borde, A. S.
    et al.
    Karlsson, E. M.
    Andersson, K.
    Bjorhall, K.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, B.
    Assessment of enzymatic prodrug stability in human, dog and simulated intestinal fluids2012In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 80, no 3, p. 630-637Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to determine the stability of three ester prodrugs, chloramphenicol succinate, enalapril and candesartan cilexetil, in human proximal small intestinal fluid (HIF), dog proximal small intestinal fluids (DIF) and simulated intestinal fluid (FaSSIF), with the addition of pancreatin. The total protein content in the proximal jejuna] fluids was determined in HIF and DIF, respectively. Candesartan cilexetil was significantly degraded in HIF (initial t(1/2(0-5min)) 5.4 +/- 0.5 min) and in DIF (initial t(1/2(0-5min))) = 5.7 +/- 0.1 min), while chloramphenicol succinate and enalapril were stable in both media. The degradation of candesartan cilexetil was shown to be mediated by enzymes following Michaelis-Menten enzyme kinetics and was inhibited by addition of esterase inhibitors. The enzymatic capacity reflected by V-max was 4-fold higher in DIF than in HIF and correlated to its 2-fold higher protein concentration. The degradation of candesartan cilexetil in the FaSSIF-pancreatin solution was slower (t(1/2) = 207 +/- 34 min) than the degradation in both HIF and DIF. Changing the pH to the enzyme optima or increasing the amount of pancreatin, increased the degradation rate of candesartan cilexetil, but not in the magnitude as in HIF. As a result, two in vitro models, based on in vivo intestinal fluids, were developed using candesartan cilexetil as a model drug. The DIF seems to be a reasonably good model for HIF, although the degradation capacity seems to be somewhat higher, possibly due to the higher enzyme concentration in DIF. Future investigations will develop novel enzymatic based in vitro models for rapid assessment and biopharmaceutical screening tools for prodrugs.

  • 21. Bouvier d'Yvoire, Michel
    et al.
    Prieto, Pilar
    Blaauboer, Bas
    Bois, Frederic
    Boobis, Alan
    Brochot, Céline
    Coecke, Sandra
    Freidig, Andreas
    Gundert-Remy, Ursula
    Hartung, Thomas
    Jacobs, Miriam
    Lavé, Thierry
    Leahy, David
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Loizou, George
    Meek, Bette
    Pease, Camilla
    Rowland, Malcolm
    Spendiff, Martin
    Yang, Jiansong
    Zeilmaker, Marco
    Physiologically-based Kinetic Modelling (PBK Modelling): Meeting the 3Rs agenda. The report and recommendations of ECVAM Workshop 632007In: ATLA (Alternatives to Laboratory Animals), ISSN 0261-1929, Vol. 35, no 6, p. 661-671Article in journal (Refereed)
  • 22.
    Bransford, Philip
    et al.
    Vertex Pharmaceut Inc, 50 Northern Ave, Boston, MA 02210 USA.
    Cook, Jack
    Pfizer Inc, Global Prod Dev, Clin Pharmacol Dept, Groton, CT 06320 USA.
    Gupta, Manish
    GlaxoSmithKline, Biopharmaceut Prod Dev & Supply, Collegeville, PA 19426 USA.
    Haertter, Sebastian
    Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA.
    He, Handan
    Novartis Inst Biomed Res, Dept Drug Metab & Pharmacokinet, E Hanover, NJ 07936 USA.
    Ju, Rob
    AbbVie, Drug Prod Dev, N Chicago, IL 60064 USA.
    Kanodia, Jitendra
    Theravance Biopharma US Inc, San Francisco, CA 94080 USA.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lindley, David
    AbbVie Inc, N Chicago, IL 60064 USA.
    Polli, James E.
    Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA.
    Wenning, Larissa
    Merck & Co Inc, MRL, Pharmacokinet Pharmacodynam & Drug Metab, West Point, PA 19486 USA.
    Wu, Yunhui
    Merck & Co Inc, MRL, Pharmaceut Sci, West Point, PA 19486 USA.
    ICH M9 Guideline in Development on Biopharmaceutics Classification System-Based Biowaivers: An Industrial Perspective from the IQ Consortium2020In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 17, no 2, p. 361-372Article in journal (Refereed)
    Abstract [en]

    In October 2016, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) ICH began efforts to provide recommendations to harmonize guidances for biopharmaceutics classification system (BCS)-based biowaivers. Topics to be addressed included consideration of the dose used to classify solubility, tests, and criteria for establishing highly permeable, dissolution conditions, the influence of excipients, and aspects of product strength. The International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) is a technically focused organization of pharmaceutical and biotechnology companies with a mission of advancing science and technology to augment the capability of member companies to develop transformational solutions that benefit patients, regulators, and the broader R&D community. Its members have substantial expertise in all scientific domains associated with BCS-based waivers and drug product quality, as well as considerable experience in the application of BCS-based biowaivers. The ICH process recognizes that harmonization is achieved through the development of guidelines via a process of scientific consensus with regulatory and industry experts working side-by-side. Thus, to facilitate these efforts and to encourage open and transparent discussion of other perspectives that may exist, IQ offers their perspective on these and related topics.

  • 23.
    Calitz, Carlemi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala Univ, Dept Med Cell Biol, Husargatan 3,Box 571, S-75431 Uppsala, Sweden..
    Rosenquist, Jenny
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Macromolecular Chemistry. Uppsala Univ, Dept Chem, Angstrom Lab, Polymer Chem, Box 538, S-75121 Uppsala, Sweden..
    Degerstedt, Oliver
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
    Khaled, Jaafar
    Uppsala Univ, Dept Med Cell Biol, Husargatan 3,Box 571, S-75431 Uppsala, Sweden..
    Kopsida, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala Univ, Dept Med Cell Biol, Husargatan 3,Box 571, S-75431 Uppsala, Sweden..
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala Univ, Dept Med Sci Canc Pharmacol & Computat Med, Uppsala, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
    Samanta, Ayan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Macromolecular Chemistry. Uppsala Univ, Dept Chem, Angstrom Lab, Polymer Chem, Box 538, S-75121 Uppsala, Sweden..
    Heindryckx, Femke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala Univ, Dept Med Cell Biol, Husargatan 3,Box 571, S-75431 Uppsala, Sweden..
    Influence of extracellular matrix composition on tumour cell behaviour in a biomimetic in vitro model for hepatocellular carcinoma2023In: Scientific Reports, E-ISSN 2045-2322, Vol. 13, no 1Article in journal (Refereed)
    Abstract [en]

    The tumor micro-environment (TME) of hepatocellular carcinoma (HCC) consists out of cirrhotic liver tissue and is characterized by an extensive deposition of extracellular matrix proteins (ECM). The evolution from a reversible fibrotic state to end-stage of liver disease, namely cirrhosis, is characterized by an increased deposition of ECM, as well as changes in the exact ECM composition, which both contribute to an increased liver stiffness and can alter tumor phenotype. The goal of this study was to assess how changes in matrix composition and stiffness influence tumor behavior. HCC-cell lines were grown in a biomimetic hydrogel model resembling the stiffness and composition of a fibrotic or cirrhotic liver. When HCC-cells were grown in a matrix resembling a cirrhotic liver, they increased proliferation and protein content, compared to those grown in a fibrotic environment. Tumour nodules spontaneously formed outside the gels, which appeared earlier in cirrhotic conditions and were significantly larger compared to those found outside fibrotic gels. These tumor nodules had an increased expression of markers related to epithelial-to-mesenchymal transition (EMT), when comparing cirrhotic to fibrotic gels. HCC-cells grown in cirrhotic gels were also more resistant to doxorubicin compared with those grown in fibrotic gels or in 2D. Therefore, altering ECM composition affects tumor behavior, for instance by increasing pro-metastatic potential, inducing EMT and reducing response to chemotherapy.

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  • 24.
    Cano-Cebrian, Maria-Jose
    et al.
    Univ Valencia, Dept Pharm Pharmaceut Technol & Parasitol, Burjassot 46100, Spain.;Uppsala Univ, Dept Pharmaceut Biosci Translat Drug Discovery &, S-75236 Uppsala, Sweden..
    Dahlgren, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kullenberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Peters, Karsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Olander, Tobias
    Uppsala Univ, Dept Pharmaceut Biosci Translat Drug Discovery &, S-75236 Uppsala, Sweden..
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Chemotherapeutics Combined with Luminal Irritants: Effects on Small-Intestinal Mannitol Permeability and Villus Length in Rats2022In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 23, no 3, article id 1021Article in journal (Refereed)
    Abstract [en]

    Chemotherapy causes intestinal mucositis, which includes villous atrophy and altered mucosal barrier function. However, there is an uncertainty regarding how the reduced small-intestinal surface area affects the mucosal permeability of the small marker probe mannitol (MW 188), and how the mucosa responds to luminal irritants after chemotherapy. The aims in this study were to determine (i) the relationship between chemotherapy-induced villus atrophy and the intestinal permeability of mannitol and (ii) how the mucosa regulate this permeability in response to luminal ethanol and sodium dodecyl sulfate (SDS). This was investigated by treating rats with a single intraperitoneal dose of doxorubicin, irinotecan, or 5-fluorouracil. After 72 h, jejunum was single-pass perfused and mannitol permeability determined at baseline and after 15 min luminal exposure to 15% ethanol or 5 mg/mL SDS. Tissue samples for morphological analyses were sampled from the perfused segment. All three chemotherapeutics caused a similar 30% reduction in villus length. Mannitol permeability increased with irinotecan (1.3-fold) and 5-fluorouracil (2.5-fold) and was reduced with doxorubicin (0.5-fold), suggesting that it is not epithelial surface area alone that regulates intestinal permeability to mannitol. There was no additional increase in mannitol permeability induced by luminal ethanol or SDS in the chemotherapy-treated rats compared to controls, which may be related to the relatively high basal permeability of mannitol compared to other common low-permeability probes. We therefore suggest that future studies should focus on elucidating the complex interplay between chemotherapy in combination with luminal irritants on the intestinal permeability of other probes.

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  • 25. Cao, Xianhua
    et al.
    Gibbs, Seth T.
    Fang, Lanyan
    Miller, Heather A.
    Landowski, Christopher P.
    Shin, Ho-Chul
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Zhong, Yanqiang
    Amidon, Gordon L.
    Yu, Lawrence X.
    Sun, Duxin
    Why is it challenging to predict intestinal drug absorption and oral bioavailability in human using rat model2006In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 23, no 8, p. 1675-1686Article in journal (Refereed)
    Abstract [en]

    Purpose. To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat.

    Materials and Methods. The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis.

    Results. No correlation (r(2) = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r(2) = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r(2) > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns.

    Conclusions. The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.

  • 26. Carlert, Sara
    et al.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    Evaluation of the use of Classical Nucleation Theory for predicting intestinal crystalline precipitation of two weakly basic BSC class II drugs2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 53, p. 17-27Article in journal (Refereed)
    Abstract [en]

    The aim of this work was to evaluate an in vitro-in silico approach for prediction of small intestinal crystalline precipitation and drug absorption of two weakly basic model BCS class II drugs, AZD0865 and mebendazole. The crystallization rates were investigated in an in vitro method using simulated gastric and intestinal media, and the result was modeled by using Classical Nucleation Theory (CNT). The effect of varying in vitro parameters (initial drug concentration, rate of mixing gastric and intestinal fluid, stirring and filtration) on the interfacial tension gamma, being a key parameter in CNT, was investigated. The initial drug concentration had the most significant effect on gamma for both substances tested, although gamma is a fundamental parameter independent of concentration according to CNT. In the subsequent in silico prediction of drug absorption, by use of a Compartmental and Transit intestinal model, an empirical approach was used where gamma was allowed to vary with simulated small intestinal concentrations. The in silico predictions were compared to published human in vivo plasma drug concentration data for different doses of AZD0865 and dog intestinal drug concentrations, amount precipitated in intestine and plasma concentrations for mebendazole. The results showed that lack of significant crystallization effects on absorption in man of the model drug AZD0865 up to doses of 4 mg/kg could be predicted which was in accordance with in vivo data. Mebendazole intestinal precipitation in canines was also well described by the model, where mean predicted amount precipitated was 136% (range 111-164%) of measured solid amount, and mean predicted intestinal concentration was 94% (range 59-147%) of measured concentration. In conclusion, the in vitro-in silico approach can be used for predictions of absorption effects of crystallization, but the model could benefit from further development work on the theoretical crystallization model and in vitro experimental design.

  • 27.
    Carlert, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pålsson, Anna
    Hanisch, Gunilla
    von Corswant, Christian
    Nilsson, Catarina
    Lindfors, Lennart
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Predicting intestinal precipitation: a case example for a basic BCS class II drug2010In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 27, no 10, p. 2119-2130Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate the prediction accuracy of in vitro and in vitro/in silico methods for in vivo intestinal precipitation of basic BCS class II drugs in humans. METHODS: Precipitation rate of a model drug substance, AZD0865 (pKa = 6.1; log K(D) = 4.2), was investigated in vitro using simulated intestinal media, and calculations of the crystallization rates were made with a theoretical model. Human intestinal precipitation was estimated by analysis of pharmacokinetic data from clinical studies at different doses. RESULTS: All in vitro models predicted rapid drug precipitation, where the intestinal concentration of dissolved AZD0865 at the highest dose tested was expected to decrease to half after less than 20 min. However, there was no indication of precipitation in vivo in humans as there was a dose proportional increase in drug plasma exposure. The theoretical model predicted no significant precipitation within the range of expected in vivo intestinal concentrations. CONCLUSIONS: This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.

  • 28.
    Carlert, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Åkesson, Pernilla
    Jerndal, Gunilla
    Lindfors, Lennart
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vivo Dog Intestinal Precipitation of Mebendazole: A Basic BCS Class II Drug2012In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 10, p. 2903-2911Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate in viva intestinal precipitation of a model drug mebendazole, a basic BCS class II drug, using dogs with intestinal stomas for administration or sampling. After oral administration of a solution with an expected intestinal supersaturation of approximately 20 times the solubility, the measured supersaturation in dog intestinal fluid (DIE) was up to 10 times and, on average, only 11% of the given dose was retrieved as solid drug in the collected fluid from the stoma. The drug was rapidly absorbed with >90% of the total systemic exposure reached within three hours after duodenal administration of a solution. In silico absorption modeling showed that in vivo data were reasonably well described by a nonprecipitating solution. An in vitro model of precipitation in DIF predicted that the intestinal concentration of dissolved mebendazole would be less than 1/5 of the initial concentration within 10 min at concentrations comparable to in vivo. It was concluded that intestinal precipitation did not have any major influence on mebendazole absorption. The extent of precipitation was overpredicted in vitro given the in vivo absorption rate, and further work is needed to identify in vitro factors that could enable more accurate in vivo predictions of intestinal precipitation from solutions.

  • 29. Chen, Mei-Ling
    et al.
    Amidon, Gordon L
    Benet, Leslie Z
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Yu, Lawrence X
    The BCS, BDDCS, and regulatory guidances2011In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 28, no 7, p. 1774-1778Article in journal (Refereed)
  • 30. Dahan, Arik
    et al.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Amidon, Gordon L.
    The Fraction Dose Absorbed, in Humans, and High Jejunal Human Permeability Relationship2012In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 6, p. 1847-1851Article in journal (Refereed)
    Abstract [en]

    The drug intestinal permeability (P-eff) measure has been widely used as one of the main factors governing both the rate and/or extent of drug absorption (F-abs) in humans following oral administration. In this communication we emphasize the complexity behind and the care that must be taken with this in vivo Puff measurement. Intestinal permeability, considering the whole of the human intestine, is more complex than generally recognized, and this can lead to misjudgment regarding F-abs and P-err in various settings, e.g. drug discovery, formulation design, drug development and regulation. Setting the adequate standard for the low/high permeability class boundary, the different experimental methods for the permeability measurement, and segmental-dependent permeability throughout the human intestine due to different mechanisms are some of the main points that are discussed. Overall, the use of jejunal P-eff as a surrogate for extent of absorption is sound and scientifically justified; a compound with high jejunal P-eff will have high F-abs, eliminating the risk for misclassification as a BCS class I drug. Much more care should be taken, however, when jejunal P-eff does not support a high-permeability classification; a thorough examination may reveal high-permeability after all, attributable to e.g. segmental-dependent permeability due to degree of ionization or transporter expression. In this situation, the use of multiple permeability experimental methods, including the use of metabolism, which except for huminal degradation requires absorption, is prudent and encouraged.

  • 31. Dahan, Arik
    et al.
    Miller, Jonathan M.
    Hilfinger, John M.
    Yamashita, Shinji
    Yu, Lawrence X.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Amidon, Gordon L.
    High-Permeability Criterion for BCS Classification: Segmental/pH Dependent Permeability Considerations2010In: Molecular pharmaceutics, ISSN 1543-8384, Vol. 7, no 5, p. 1827-1834Article in journal (Refereed)
    Abstract [en]

    The FDA classifies a drug substance as high-permeability when the fraction of dose absorbed (F-abs) in humans is 90% or higher. This direct correlation between human permeability and Fab, has been recently controversial, since the beta-blocker sotalol showed high F-abs (90%) and low Caco-2 permeability. The purpose of this study was to investigate the scientific basis for this disparity between permeability and F-abs. The effective permeabilities (P-eff) of sotalol and metoprolol, a FDA standard for the low/high P-off class boundary, were investigated in the rat perfusion model, in three different intestinal segments with pHs corresponding to the physiological pH in each region: (1) proximal jejunum, pH 6.5; (2) mid small intestine, pH 7.0; and (3) distal ileum, pH 7.5. Both metoprolol and sotalol showed pH-dependent permeability, with higher P-eff at higher pH. At any given pH, sotalol showed lower permeability than metoprolol; however, the permeability of sotalol determined at pH 7.5 exceeded/matched metoprolol's at pH 6.5 and 7.0, respectively. Physicochemical analysis based on ionization, pK(a) and partitioning of these drugs predicted the same trend and clarified the mechanism behind these observed results. Experimental octanol buffer partitioning experiments confirmed the theoretical curves. An oral dose of metoprolol has been reported to be completely absorbed in the upper small intestine; it follows, hence, that metoprolol's P-eff, value at pH 7.5 is not likely physiologically relevant for an immediate release dosage form, and the permeability at pH 6.5 represents the actual relevant value for the low/high permeability class boundary. Although sotalol's permeability is low at pH 6,5 and 7.0, at pH 7.5 it exceeds/matches the threshold of metoprolol at pH 6.5 and 7.0, most likely responsible for its high Faros, In conclusion, we have shown that, in fact, there is no discrepancy between P-eff and F-abs, in sotalol's absorption; the data emphasize that, if a compound has high fraction of dose absorbed, it will have high-permeability, not necessarily in the jejunum, but at some point along the relevant intestinal regions.

  • 32.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Cano-Cebrian, Maria-Jose
    Univ Valencia, Dept Pharm Pharmaceut Technol & Parasitol, Valencia 46010, Spain..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Wanders, Alkwin
    Aalborg Univ Hosp, Dept Pathol, DK-9100 Aalborg, Denmark..
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Prevention of Rat Intestinal Injury with a Drug Combination of Melatonin and Misoprostol2020In: International Journal of Molecular Sciences, ISSN 1661-6596, E-ISSN 1422-0067, Vol. 21, no 18, article id 6771Article in journal (Refereed)
    Abstract [en]

    A healthy intestinal barrier prevents uptake of allergens and toxins, whereas intestinal permeability increases following chemotherapy and in many gastrointestinal and systemic diseases and disorders. Currently, there are no approved drugs that target and repair the intestinal epithelial barrier while there is a medical need for such treatment in gastrointestinal and related conditions. The objective of this single-pass intestinal perfusion study in rats was to investigate the preventive cytoprotective effect of three mucosal protective drugs-melatonin, misoprostol, and teduglutide-with different mechanisms of action on an acute jejunal injury induced by exposing the intestine for 15 min to the anionic surfactant, sodium dodecyl sulfate (SDS). The effect was evaluated by monitoring intestinal clearance of Cr-51-labeled ethylenediaminetetraacetate and intestinal histology before, during, and after luminal exposure to SDS. Our results showed that separate pharmacological pretreatments with luminal misoprostol and melatonin reduced acute SDS-induced intestinal injury by 47% and 58%, respectively, while their use in combination abolished this injury. This data supports further development of drug combinations for oral treatments of conditions and disorders related to a dysregulated or compromised mucosal epithelial barrier.

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  • 33.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Cano-Cebrian, Maria-Jose
    Univ Valencia, Dept Pharm & Pharmaceut Technol & Parasitol, Valencia 46010, Spain..
    Olander, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden..
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat2020In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 12, no 3, article id 242Article in journal (Refereed)
    Abstract [en]

    Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers-sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate-on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs.

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  • 34.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective2020In: Molecules, ISSN 1431-5157, E-ISSN 1420-3049, Vol. 25, no 12, article id 2861Article, review/survey (Refereed)
    Abstract [en]

    Increased understanding of cancer biology, pharmacology and drug delivery has provided a new framework for drug discovery and product development that relies on the unique expression of specific macromolecules (i.e., antigens) on the surface of tumour cells. This has enabled the development of anti-cancer treatments that combine the selectivity of antibodies with the efficacy of highly potent chemotherapeutic small molecules, called antibody-drug conjugates (ADCs). ADCs are composed of a cytotoxic drug covalently linked to an antibody which then selectively binds to a highly expressed antigen on a cancer cell; the conjugate is then internalized by the cell where it releases the potent cytotoxic drug and efficiently kills the tumour cell. There are, however, many challenges in the development of ADCs, mainly around optimizing the therapeutic/safety benefits. These challenges are discussed in this review; they include issues with the plasma stability and half-life of the ADC, its transport from blood into and distribution throughout the tumour compartment, cancer cell antigen expression and the ADC binding affinity to the target antigen, the cell internalization process, cleaving of the cytotoxic drug from the ADC, and the cytotoxic effect of the drug on the target cells. Finally, we present a summary of some of the experimental ADC strategies used in the treatment of hepatocellular carcinoma, from the recent literature.

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  • 35.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Intestinal Permeability and Drug Absorption: Predictive Experimental, Computational and In Vivo Approaches2019In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 11, no 8, article id 411Article, review/survey (Refereed)
    Abstract [en]

    The main objective of this review is to discuss recent advancements in the overall investigation and in vivo prediction of drug absorption. The intestinal permeability of an orally administered drug (given the value P-eff) has been widely used to determine the rate and extent of the drug's intestinal absorption (F-abs) in humans. Preclinical gastrointestinal (GI) absorption models are currently in demand for the pharmaceutical development of novel dosage forms and new drug products. However, there is a strong need to improve our understanding of the interplay between pharmaceutical, biopharmaceutical, biochemical, and physiological factors when predicting F-abs and bioavailability. Currently, our knowledge of GI secretion, GI motility, and regional intestinal permeability, in both healthy subjects and patients with GI diseases, is limited by the relative inaccessibility of some intestinal segments of the human GI tract. In particular, our understanding of the complex and highly dynamic physiology of the region from the mid-jejunum to the sigmoid colon could be significantly improved. One approach to the assessment of intestinal permeability is to use animal models that allow these intestinal regions to be investigated in detail and then to compare the results with those from simple human permeability models such as cell cultures. Investigation of intestinal drug permeation processes is a crucial biopharmaceutical step in the development of oral pharmaceutical products. The determination of the intestinal P-eff for a specific drug is dependent on the technique, model, and conditions applied, and is influenced by multiple interactions between the drug molecule and the biological membranes.

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  • 36.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Review on the effect of chemotherapy on the intestinal barrier: Epithelial permeability, mucus and bacterial translocation2023In: Biomedicine and Pharmacotherapy, ISSN 0753-3322, E-ISSN 1950-6007, Vol. 162, article id 114644Article, review/survey (Refereed)
    Abstract [en]

    Chemotherapy kills fast-growing cells including gut stem cells. This affects all components of the physical and functional intestinal barrier, i.e., the mucus layer, epithelium, and immune system. This results in an altered intestinal permeability of toxic compounds (e.g., endotoxins) as well as luminal bacterial translocation into the mucosa and central circulation. However, there is uncertainty regarding the relative contributions of the different barrier components for the development of chemotherapy-induced gut toxicity. This review present an overview of the intestinal mucosal barrier determined with various types of molecular probes and methods, and how they are affected by chemotherapy based on reported rodent and human data. We conclude that there is overwhelming evidence that chemotherapy increases bacterial translocation, and that it affects the mucosal barrier by rendering the mucosa more permeable to large permeability probes. Chemotherapy also seems to impede the intestinal mucus barrier, even though this has been less clearly evaluated from a functional stand-point but certainly plays a role in bacteria translocation. Combined, it is however difficult to outline a clear temporal or succession between the different gastrointestinal events and barrier functions, especially as chemotherapy-induced neutropenia is also involved in intestinal immunological homeostasis and bacterial translocation. A thorough characterization of this would need to include a time dependent development of neutropenia, intestinal permeability, and bacterial translocation, ideally after a range of chemotherapeutics and dosing regimens.

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    fulltext
  • 37.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Olander, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, S-75189 Uppsala, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Effect of paracellular permeation enhancers on intestinal permeability of two peptide drugs, enalaprilat and hexarelin, in rats2021In: Acta Pharmaceutica Sinica B, ISSN 2211-3835, E-ISSN 2211-3843, Vol. 11, no 6, p. 1667-1675Article in journal (Refereed)
    Abstract [en]

    Transcellular permeation enhancers are known to increase the intestinal permeability of enalaprilat, a 349 Da peptide, but not hexarelin (887 Da). The primary aim of this paper was to investigate if paracellular permeability enhancers affected the intestinal permeation of the two peptides. This was investigated using the rat single-pass intestinal perfusion model with concomitant blood sampling. These luminal compositions included two paracellular permeation enhancers, chitosan (5 mg/mL) and ethylenediaminetetraacetate (EDTA, 1 and 5 mg/mL), as well as low luminal tonicity (100 mOsm) with or without lidocaine. Effects were evaluated by the change in lumen-to-blood permeability of hexarelin and enalaprilat, and the blood-to-lumen clearance of (51)chromium-labeled EDTA (CLCr-EDTA), a clinical marker for mucosal barrier integrity. The two paracellular permeation enhancers increased the mucosal permeability of both peptide drugs to a similar extent. The data in this study suggests that the potential for paracellular permeability enhancers to increase intestinal absorption of hydrophilic peptides with low molecular mass is greater than for those with transcellular mechanism-of-action. Further, the mucosal blood-to-lumen flux of Cr-51-EDTA was increased by the two paracellular permeation enhancers and by luminal hypotonicity. In contrast, luminal hypotonicity did not affect the lumen-to-blood transport of enalaprilat and hexarelin. This suggests that hypotonicity affects paracellular solute transport primarily in the mucosal crypt region, as this area is protected from luminal contents by a constant water flow from the crypts.

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  • 38.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johansson, P
    Tannergren, C
    Lundqvist, A
    Langguth, P
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The effects of three absorption-modifying critical excipients on the in vivo intestinal absorption of six model compounds in rats and dogs.2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 547, no 1-2, p. 158-168Article in journal (Refereed)
    Abstract [en]

    Pharmaceutical excipients that may affect gastrointestinal (GI) drug absorption are called critical pharmaceutical excipients, or absorption-modifying excipients (AMEs) if they act by altering the integrity of the intestinal epithelial cell membrane. Some of these excipients increase intestinal permeability, and subsequently the absorption and bioavailability of the drug. This could have implications for both the assessment of bioequivalence and the efficacy of the absorption-enhancing drug delivery system. The absorption-enhancing effects of AMEs with different mechanisms (chitosan, sodium caprate, sodium dodecyl sulfate (SDS)) have previously been evaluated in the rat single-pass intestinal perfusion (SPIP) model. However, it remains unclear whether these SPIP data are predictive in a more in vivo like model. The same excipients were in this study evaluated in rat and dog intraintestinal bolus models. SDS and chitosan did exert an absorption-enhancing effect in both bolus models, but the effect was substantially lower than those observed in the rat SPIP model. This illustrates the complexity of the AME effects, and indicates that additional GI physiological factors need to be considered in their evaluation. We therefore recommend that AME evaluations obtained in transit-independent, preclinical permeability models (e.g. Ussing, SPIP) should be verified in animal models better able to predict in vivo relevant GI effects, at multiple excipient concentrations.

  • 39.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johansson, Pernilla
    AstraZeneca R&D, SE-43150 Gothenburg, Sweden..
    Lundqvist, Anders
    AstraZeneca R&D, SE-43150 Gothenburg, Sweden..
    Tannergren, Christer
    AstraZeneca R&D, SE-43150 Gothenburg, Sweden..
    Abraharnsson, Bertil
    AstraZeneca R&D, SE-43150 Gothenburg, Sweden..
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional Intestinal Permeability in Dogs: Biopharmaceutical Aspects for Development of Oral Modified-Release Dosage Forms2016In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 9, p. 3022-3033Article in journal (Refereed)
    Abstract [en]

    The development of oral modified-release (MR) dosage forms requires an active pharmaceutical ingredient (API) with a sufficiently high absorption rate in both the small and large intestine. Dogs are commonly used in preclinical evaluation of regional intestinal absorption and in the development of novel MR dosage forms. This study determined regional intestinal effective permeability (P-eff) in dogs with the aim to improve regional Peff prediction in humans. Four model drugs, atenolol, enalaprilat, metoprolol, and ketoprofen, were intravenously and regionally dosed twice as a solution into the proximal small intestine (P-SI) and large intestine (LI) of three dogs with intestinal stomas. Based on plasma data from two separate study occasions for each dog, regional Peff values were calculated using a validated intestinal deconvolution method. The determined mean P-eff values were 0.62, 0.14, 1.06, and 3.66 X 10(-4) cm/s in the P-SI, and 0.13, 0.02, 1.03, and 2.20 X 10(-4) cm/s in the LI, for atenolol, enalaprilat, metoprolol, and ketoprofen, respectively. The determined P-SI Peff values in dog were highly correlated (R-2 = 0.98) to the historically directly determined human jejunal P-eff after a single-pass perfusion. The determined dog P-SI P-eff values were also successfully implemented in GI-Sim to predict the risk for overestimation of LI absorption of low permeability drugs. We conclude that the dog intestinal stoma model is a useful preclinical tool for determination of regional intestinal permeability. Still, further studies are recommended to evaluate additional APIs, sources of variability, and formulation types, for more accurate determination of the dog model in the drug development process.

  • 40.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, A
    AstraZeneca R&D, Gothenburg, Sweden.
    Tannergren, C
    AstraZeneca R&D, Gothenburg, Sweden.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of absorption-modifying excipients, hypotonicity, and enteric neural activity in an in vivo model for small intestinal transport.2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 549, no 1-2, p. 239-248, article id S0378-5173(18)30532-5Article in journal (Refereed)
    Abstract [en]

    The small intestine mucosal barrier is physiologically regulated by the luminal conditions, where intestinal factors, such as diet and luminal tonicity, can affect mucosal permeability. The intestinal barrier may also be affected by absorption-modifying excipients (AME) in oral drug delivery systems. Currently, there is a gap in the understanding of how AMEs interact with the physiological regulation of intestinal electrolyte transport and fluid flux, and epithelial permeability. Therefore, the objective of this single-pass perfusion study in rat was to investigate the effect of three AMEs on the intestinal mucosal permeability at different luminal tonicities (100, 170, and 290 mOsm). The effect was also evaluated following luminal administration of a nicotinic receptor antagonist, mecamylamine, and after intravenous administration of a COX-2 inhibitor, parecoxib, both of which affect the enteric neural activity involved in physiological regulation of intestinal functions. The effect was evaluated by changes in intestinal lumen-to-blood transport of six model compounds, and blood-to-lumen clearance of 51Cr-EDTA (a mucosal barrier marker). Luminal hypotonicity alone increased the intestinal epithelial transport of 51Cr-EDTA. This effect was potentiated by two AMEs (SDS and caprate) and by parecoxib, while it was reduced by mecamylamine. Consequently, the impact of enteric neural activity and luminal conditions may affect nonclinical determinations of intestinal permeability. In vivo predictions based on animal intestinal perfusion models can be improved by considering these effects. The in vivo relevance can be increased by treating rats with a COX-2 inhibitor prior to surgery. This decreases the risk of surgery-induced ileus, which may affect the physiological regulation of mucosal permeability.

  • 41.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, A.
    Tannergren, C.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Time-dependent effects on small intestinal transport by absorption-modifying excipients2018In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 132, p. 19-28Article in journal (Refereed)
    Abstract [en]

    The relevance of the rat single-pass intestinal perfusion model for investigating in vivo time-dependent effects of absorption-modifying excipients (AMEs) is not fully established. Therefore, the dynamic effect and recovery of the intestinal mucosa was evaluated based on the lumen-to-blood flux (Jabs) of six model compounds, and the blood-to-lumen clearance of 51Cr-EDTA (CLCr), during and after 15- and 60-min mucosal exposure of the AMEs, sodium dodecyl sulfate (SDS) and chitosan, in separate experiments. The contribution of enteric neurons on the effect of SDS and chitosan was also evaluated by luminal coadministration of the nicotinic receptor antagonist, mecamylamine. The increases in Jabs and CLCr (maximum and total) during the perfusion experiments were dependent on exposure time (15 and 60 min), and the concentration of SDS, but not chitosan. The increases in Jabs and CLCr following the 15-min intestinal exposure of both SDS and chitosan were greater than those reported from an in vivo rat intraintestinal bolus model. However, the effect in the bolus model could be predicted from the increase of Jabs at the end of the 15-min exposure period, where a six-fold increase in Jabs was required for a corresponding effect in the in vivo bolus model. This illustrates that a rapid and robust effect of the AME is crucial to increase the in vivo intestinal absorption rate before the yet unabsorbed drug in lumen has been transported distally in the intestine. Further, the recovery of the intestinal mucosa was complete following 15-min exposures of SDS and chitosan, but it only recovered 50% after the 60-min intestinal exposures. Our study also showed that the luminal exposure of AMEs affected the absorptive model drug transport more than the excretion of 51Cr-EDTA, as Jabs for the drugs was more sensitive than CLCr at detecting dynamic mucosal AME effects, such as response rate and recovery. Finally, there appears to be no nicotinergic neural contribution to the absorption-enhancing effect of SDS and chitosan, as luminal administration of 0.1 mM mecamylamine had no effect.

  • 42.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, Anders
    AstraZeneca R&D, Gothenburg, Sweden..
    Abrahamsson, Bertil
    AstraZeneca R&D, Gothenburg, Sweden..
    Tannergren, Christer
    AstraZeneca R&D, Gothenburg, Sweden..
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional Intestinal Permeability of Three Model Drugs in Human2016In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 9, p. 3013-3021Article in journal (Refereed)
    Abstract [en]

    Currently there are only a limited number of determinations of human P-eff in the distal small intestine and none in the large intestine. This has hindered the validation of preclinical models with regard to absorption in the distal parts of the intestinal tract, which can be substantial for BCS class II-IV drugs, and drugs formulated into modified-release (MR) dosage forms. To meet this demand, three model drugs (atenolol, metoprolol, and ketoprofen) were dosed in solution intravenously, and into the jejunum, ileum, and colon of 14 healthy volunteers. The P-eff of each model drug was then calculated using a validated deconvolution method. The median P-eff of atenolol in the jejunum, ileum, and colon was 0.45, 0.15, and 0.013 X 10(-4) cm/s, respectively. The corresponding values for metoprolol were 1.72, 0.72, and 1.30 X 10(-4) cm/s, and for ketoprofen 8.85, 6.53, and 3.37 X 10(-4) cm/s, respectively. This is the first study where the human Peff of model drugs has been determined in all parts of the human intestinal tract in the same subjects. The jejunal values were similar to directly determined values using intestinal single-pass perfusion, indicating that the deconvolution method is a valid approach for determining regional P-eff. The values from this study will be highly useful in the validation of preclinical regional absorption models and in silico tools.

  • 43.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, Anders
    AstraZeneca R&D.
    Tannergren, Christer
    AstraZeneca R&D.
    Langguth, Peter
    School of Pharmacy, Johannes Gutenberg-University, 55122 Mainz, Germany.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Preclinical Effect of Absorption Modifying Excipients on Rat Intestinal Transport of Model Compounds and the Mucosal Barrier Marker 51Cr-EDTA2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4243-4251Article in journal (Refereed)
    Abstract [en]

    There is a renewed interest from the pharmaceutical field to develop oral formulations of compounds, such as peptides, oligonucleotides, and polar drugs. However, these often suffer from insufficient absorption across the intestinal mucosal barrier. One approach to circumvent this problem is the use of absorption modifying excipient(s) (AME). This study determined the absorption enhancing effect of four AMEs (sodium dodecyl sulfate, caprate, chitosan, N-acetylcysteine) on five model compounds in a rat jejunal perfusion model. The aim was to correlate the model compound absorption to the blood-to-lumen clearance of the mucosal marker for barrier integrity, 51Cr-EDTA. Sodium dodecyl sulfate and chitosan increased the absorption of the low permeation compounds but had no effect on the high permeation compound, ketoprofen. Caprate and N-acetylcysteine did not affect the absorption of any of the model compounds. The increase in absorption of the model compounds was highly correlated to an increased blood-to-lumen clearance of 51Cr-EDTA, independent of the AME. Thus, 51Cr-EDTA could be used as a general, sensitive, and validated marker molecule for absorption enhancement when developing novel formulations.

  • 44.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Peters, Karsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundqvist, A.
    AstraZeneca R&D, Gothenburg, Sweden.
    Tannergren, C.
    AstraZeneca R&D, Gothenburg, Sweden.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Evaluation of drug permeability calculation based on luminal disappearance and plasma appearance in the rat single-pass intestinal perfusion model2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 31-37Article in journal (Refereed)
    Abstract [en]

    The rat single-pass intestinal perfusion (SPIP) model is commonly used to investigate gastrointestinal physiology and membrane drug transport. The SPIP model can be used with the intestinal segment inside or outside the abdomen. The rats can also be treated with parecoxib, a selective cycloxygenase-2 inhibitor that has been shown to affect some intestinal functions following abdominal surgery, such as motility, epithelial permeability, fluid flux and ion transport. However, the impact of extra-abdominal placement of the intestinal segment in combination with parecoxib on intestinal drug transport has not been investigated. There is also uncertainty how well intestinal permeability determinations based on luminal drug disappearance and plasma appearance correlate in the rat SPIP model. The main objective of this rat in vivo study was to investigate the effect of intra- vs. extra abdominal SPIP, with and without, pretreatment with parecoxib. The effect was evaluated by determining the difference in blood-to-lumen Cr-51-EDTA clearance, lumen-to-blood permeability of a cassette-dose of four model compounds (atenolol, enalaprilat, ketoprofen, and metoprolol), and water flux. The second objective was to compare the jejunal permeability values of the model drugs when determined based on luminal disappearance or plasma appearance. The study showed that the placement of the perfused jejunal segment, or the treatment with parecoxib, had minimal effects on membrane permeability and water flux. It was also shown that intestinal permeability of low permeability compounds should be determined on the basis of data from plasma appearance rather than lumina] disappearance. If permeability is calculated on the basis of luminal disappearance, it should preferably include negative values to increase the accuracy in the determinations.

  • 45.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Direct In Vivo Human Intestinal Permeability (P-eff) Determined with Different Clinical Perfusion and Intubation Methods2015In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 104, no 9, p. 2702-2726Article, review/survey (Refereed)
    Abstract [en]

    Regional in vivo human intestinal effective permeability (P-eff) is calculated by measuring the disappearance rate of substances during intestinal perfusion. P-eff is the most relevant parameter in the prediction of rate and extent of drug absorption from all parts of the intestine. Today, human intestinal perfusions are not performed on a routine basis in drug development. Therefore, it would be beneficial to increase the accuracy of the in vitro and in silico tools used to evaluate the intestinal P-eff of novel drugs. This review compiles historical P-eff data from 273 individual measurements of 80 substances from 61 studies performed in all parts of the human intestinal tract. These substances include: drugs, monosaccharaides, amino acids, dipeptides, vitamins, steroids, bile acids, ions, fatty acids, and water. The review also discusses the determination and prediction of P-eff using in vitro and in silico methods such as quantitative structure-activity relationship, Caco-2, Ussing chamber, animal intestinal perfusion, and physiologically based pharmacokinetic (PBPK) modeling. Finally, we briefly outline how to acquire accurate human intestinal P-eff data by deconvolution of plasma concentration-time profiles following regional intestinal bolus dosing.

  • 46.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rosenqvist, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kullenberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Peters, Karsten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Evaluation and validation of chemotherapy‐specific diarrhoea and histopathology in rats2022In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843Article in journal (Refereed)
    Abstract [en]

    Chemotherapy-induced mucositis is characterized by diarrhoea and villous atrophy. However, it is not well-understood why diarrhoea arises, why it only occurs with some chemotherapeutics and how it is related to villus atrophy. The objectives in this study were to determine (i) the relationship between chemotherapy-induced diarrhoea and villus atrophy and to (ii) establish and validate a rat diarrhoea model with clinically relevant endpoints. Male Wistar Han IGS rats were treated with saline, doxorubicin, idarubicin, methotrexate, 5-fluorouracil, irinotecan or 5-fluorouracil+irinotecan. After 72 h, jejunal tissue was taken for morphological, apoptotic and proliferative analyses, and faecal water content and change in body weight were determined. All treatments except methotrexate caused a similar reduction (≈42%) in villus height, but none of them altered mucosal crypt cell proliferation or apoptosis. Doxorubicin, idarubicin, irinotecan and 5-fluorouracil+irinotecan caused body weight reduction, but only irinotecan and idarubicin caused diarrhoea. No direct correlation between diarrhoea and villus height or body weight loss was observed. Therefore, studies of the mechanisms for chemotherapy-induced diarrhoea should focus on functional factors. Finally, the irinotecan and idarubicin diarrhoea models established in this study will be useful in developing supportive treatments of this common and serious adverse effect in patients undergoing chemotherapy.

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  • 47.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Hedeland, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry. Natl Vet Inst SVA, S-75189 Uppsala, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The In Vivo Effect of Transcellular Permeation Enhancers on the Intestinal Permeability of Two Peptide Drugs Enalaprilat and Hexarelin2020In: Pharmaceutics, ISSN 1999-4923, E-ISSN 1999-4923, Vol. 12, no 2, article id 99Article in journal (Refereed)
    Abstract [en]

    Permeation enhancers like sodium dodecyl sulfate (SDS) and caprate increase the intestinal permeability of small model peptide compounds, such as enalaprilat (349 Da). However, their effects remain to be investigated for larger low-permeability peptide drugs, such as hexarelin (887 Da). The objective of this single-pass perfusion study in rat was to investigate the effect of SDS at 5 mg/mL and of caprate administered at different luminal concentrations (5, 10, and 20 mg/mL) and pH (6.5 and 7.4). The small intestinal permeability of enalaprilat increased by 8- and 9-fold with SDS at 5 mg/mL and with caprate at 10 and 20 mg/mL but only at pH 7.4, where the free dissolved caprate concentration is higher than at pH 6.5 (5 vs. 2 mg/mL). Neither SDS nor caprate at any of the investigated luminal concentrations enhanced absorption of the larger peptide hexarelin. These results show that caprate requires doses above its saturation concentration (a reservoir suspension) to enhance absorption, most likely because dissolved caprate itself is rapidly absorbed. The absent effect on hexarelin may partly explain why the use of permeation enhancers for enabling oral peptide delivery has largely failed to evolve from in vitro evaluations into approved oral products. It is obvious that more innovative and effective drug delivery strategies are needed for this class of drugs.

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  • 48.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Dept Pharmaceut Biosci, Uppsala, Sweden..
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Hellström, Per M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Chemotherapeutics-Induced Intestinal Mucositis: Pathophysiology and Potential Treatment Strategies2021In: Frontiers in Pharmacology, E-ISSN 1663-9812, Vol. 12, article id 681417Article, review/survey (Refereed)
    Abstract [en]

    The gastrointestinal tract is particularly vulnerable to off-target effects of antineoplastic drugs because intestinal epithelial cells proliferate rapidly and have a complex immunological interaction with gut microbiota. As a result, up to 40-100% of all cancer patients dosed with chemotherapeutics experience gut toxicity, called chemotherapeutics-induced intestinal mucositis (CIM). The condition is associated with histological changes and inflammation in the mucosa arising from stem-cell apoptosis and disturbed cellular renewal and maturation processes. In turn, this results in various pathologies, including ulceration, pain, nausea, diarrhea, and bacterial translocation sepsis. In addition to reducing patient quality-of-life, CIM often leads to dose-reduction and subsequent decrease of anticancer effect. Despite decades of experimental and clinical investigations CIM remains an unsolved clinical issue, and there is a strong consensus that effective strategies are needed for preventing and treating CIM. Recent progress in the understanding of the molecular and functional pathology of CIM had provided many new potential targets and opportunities for treatment. This review presents an overview of the functions and physiology of the healthy intestinal barrier followed by a summary of the pathophysiological mechanisms involved in the development of CIM. Finally, we highlight some pharmacological and microbial interventions that have shown potential. Conclusively, one must accept that to date no single treatment has substantially transformed the clinical management of CIM. We therefore believe that the best chance for success is to use combination treatments. An optimal combination treatment will likely include prophylactics (e.g., antibiotics/probiotics) and drugs that impact the acute phase (e.g., anti-oxidants, apoptosis inhibitors, and anti-inflammatory agents) as well as the recovery phase (e.g., stimulation of proliferation and adaptation).

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    FULLTEXT01
  • 49.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sjöblom, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Sjöblom/Nylander: Gastrointestinal Physiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Intestinal absorption-modifying excipients: A current update on preclinical in vivo evaluations2019In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 142, p. 411-420Article in journal (Refereed)
    Abstract [en]

    Pharmaceutical excipients in drug products are defined as pharmacologically inactive and are integral constituents of all types of oral dosage forms. However, some excipients may increase drug absorption by interacting with the mucosal membrane. If the strategy is to use an excipient with a potential to affect the processes determining the rate and/or extent of the intestinal drug absorption, it is defined as an absorption-modifying excipients (AME). These pharmaceutical excipients may act as AMEs, depending on the amounts applied, and accordingly influence bioequivalence assessment of innovative and generic drug products, as well as enable oral delivery of peptides and oligonucleotides. This review discusses the mechanisms by which AMEs increase drug absorption, and especially permeation step. The focus is on the most recent data regarding how AMEs can be evaluated in preclinical models, with an emphasis on in situ and in vivo intestinal absorption models. The in vivo predictive value of these models is reviewed for five factors of clinical relevance for the intestinal absorption performance: (a) effect and response rate of AMEs, (b) mucosal exposure time and intestinal transit of AMEs, (c) intraluminal AME dilution and prandial state, (d) mucosa] recovery and safety, and (e) variability in the effects of the AMEs. We argue that any preclinical investigations of AMEs that fail to consider these processes will ultimately be of limited clinical value and add little to our understanding of how excipients affect intestinal drug absorption.

  • 50.
    Dahlgren, David
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Drug Design and Discovery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Intestinal absorption of BCS class II drugs administered as nanoparticles: A review based on in vivo data from intestinal perfusion models2020In: ADMET & DMPK, ISSN 1848-7718, Vol. 8, no 4, p. 375-390Article, review/survey (Refereed)
    Abstract [en]

    An established pharmaceutical strategy to increase oral drug absorption of low solubility-high permeability drugs is to create nanoparticles of them. Reducing the size of the solid-state particles increases their dissolution and transport rate across the mucus barrier and the aqueous boundary layer. Suspensions of nanoparticles also sometimes behave differently than those of larger particles in the fed state. This review compares the absorption mechanisms of nano- and larger particles in the lumen at different prandial states, with an emphasis on data derived from in vivo models. Four BSC class II drugs-aprepitant, cyclosporine, danazol and fenofibrate-are discussed in detail based on information from preclinical intestinal perfusion models.

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