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  • 1.
    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.

  • 2.
    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.

  • 3.
    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.

  • 4. 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.

  • 5.
    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.

  • 6.
    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)
  • 7.
    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.

  • 8.
    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)
  • 9. 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.

  • 10. 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)
  • 11. 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.

  • 12. 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.

  • 13.
    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.

  • 14. 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.

  • 15.
    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.

  • 16.
    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.

  • 17.
    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.

  • 18.
    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.

  • 19.
    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.

  • 20.
    Darwich, Adam S.
    et al.
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Margolskee, Alison
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Pepin, Xavier
    AstraZeneca, London, England;Sanofi, Paris, France.
    Aarons, Leon
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Galetin, Aleksandra
    Univ Manchester, Manchester M13 9PL, Lancs, England.
    Rostami-Hodjegan, Amin
    Univ Manchester, Manchester M13 9PL, Lancs, England;Simcyp Ltd, Sheffield, S Yorkshire, England.
    Carlert, Sara
    AstraZeneca, Gothenburg, Sweden.
    Hammarberg, Maria
    AstraZeneca, Gothenburg, Sweden.
    Hilgendorf, Constanze
    AstraZeneca, Gothenburg, Sweden.
    Johansson, Pernilla
    AstraZeneca, Gothenburg, Sweden.
    Karlsson, Eva
    AstraZeneca, Gothenburg, Sweden.
    Murphy, Donal
    AstraZeneca, London, England.
    Tannergren, Christer
    AstraZeneca, Gothenburg, Sweden.
    Thorn, Helena
    AstraZeneca, Gothenburg, Sweden.
    Yasin, Mohammed
    AstraZeneca, London, England.
    Mazuir, Florent
    Sanofi, Paris, France.
    Nicolas, Olivier
    Sanofi, Paris, France.
    Ramusovic, Sergej
    Sanofi, Frankfurt, Germany.
    Xu, Christine
    Sanofi, Bridgewater, NJ USA.
    Pathak, Shriram M.
    Simcyp Ltd, Sheffield, S Yorkshire, England.
    Korjamo, Timo
    Orion Pharma, Espoo, Finland.
    Laru, Johanna
    Orion Pharma, Espoo, Finland;AstraZeneca, London, England.
    Malkki, Jussi
    Orion Pharma, Espoo, Finland.
    Pappinen, Sari
    Orion Pharma, Espoo, Finland.
    Tuunainen, Johanna
    Orion Pharma, Espoo, Finland.
    Dressman, Jennifer
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Hansmann, Simone
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    Kostewicz, Edmund
    Goethe Univ Frankfurt Am Main, Frankfurt, Germany.
    He, Handan
    Novartis, New York, NY USA.
    Heimbach, Tycho
    Novartis, New York, NY USA.
    Wu, Fan
    Novartis, New York, NY USA.
    Hoft, Carolin
    AbbVie, Wiesbaden, Germany.
    Pang, Yan
    AbbVie, Wiesbaden, Germany.
    Bolger, Michael B.
    Simulat Plus Inc, Lancaster, CA USA.
    Huehn, Eva
    Simulat Plus Inc, Lancaster, CA USA.
    Lukacova, Viera
    Simulat Plus Inc, Lancaster, CA USA.
    Mullin, James M.
    Simulat Plus Inc, Lancaster, CA USA.
    Szeto, Ke X.
    Simulat Plus Inc, Lancaster, CA USA.
    Costales, Chester
    Pfizer, New York, NY USA.
    Lin, Jian
    Pfizer, New York, NY USA.
    McAllister, Mark
    Pfizer, Tadworth, Middx, England.
    Modi, Sweta
    Pfizer, New York, NY USA.
    Rotter, Charles
    Pfizer, New York, NY USA.
    Varma, Manthena
    Pfizer, Tadworth, Middx, England.
    Wong, Mei
    Pfizer, Tadworth, Middx, England.
    Mitra, Amitava
    Merck Sharp & Dohme Ltd, Hoddesdon, Herts, England.
    Bevernage, Jan
    Janssen, Beerse, Belgium.
    Biewenga, Jeike
    Janssen, Beerse, Belgium.
    Van Peer, Achiel
    Janssen, Beerse, Belgium.
    Lloyd, Richard
    GlaxoSmithKline, Brentford, Middx, England.
    Shardlow, Carole
    GlaxoSmithKline, Brentford, Middx, England.
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Mishenzon, Irina
    Johannes Gutenberg Univ Mainz, Mainz, Germany.
    Nguyen, Mai Anh
    Brown, Jonathan
    Bristol Myers Squibb, Uxbridge, Middx, England.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, Bertil
    AstraZeneca, Gothenburg, Sweden.
    IMI - Oral biopharmaceutics tools project - Evaluation of bottom-up PBPK prediction success part 3: Identifying gaps in system parameters by analysing In Silico performance across different compound classes2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 96, p. 626-642Article in journal (Refereed)
    Abstract [en]

    Three Physiologically Based Pharmacokinetic software packages (GI-Sim, Simcyp (R) Simulator, and GastroPlus (TM)) were evaluated as part of the Innovative Medicine Initiative Oral Biopharmaceutics Tools project (OrBiTo) during a blinded "bottom-up" anticipation of human pharmacokinetics. After data analysis of the predicted vs. measured pharmacokinetics parameters, it was found that oral bioavailability (F-oral) was underpredicted for compounds with low permeability, suggesting improper estimates of intestinal surface area, colonic absorption and/or lack of intestinal transporter information. Foralwas also underpredicted for acidic compounds, suggesting overestimation of impact of ionisation on permeation, lack of information on intestinal transporters, or underestimation of solubilisation of weak acids due to less than optimal intestinal model pH settings or underestimation of bile micelle contribution. F-oral was overpredicted for weak bases, suggesting inadequate models for precipitation or lack of in vitro precipitation information to build informed models. Relative bioavailability was underpredicted for both high logP compounds as well as poorly water-soluble compounds, suggesting inadequate models for solubility/dissolution, underperforming bile enhancement models and/or lack of biorelevant solubility measurements. These results indicate areas for improvement in model software, modelling approaches, and generation of applicable input data. However, caution is required when interpreting the impact of drug-specific properties in this exercise, as the availability of input parameters was heterogeneous and highly variable, and the modellers generally used the data "as is" in this blinded bottom-up prediction approach.

  • 21. Di, Li
    et al.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Avdeef, Alex
    Ecker, Gerhard F.
    Faller, Bernard
    Fischer, Holger
    Houston, J. Brian
    Kansy, Manfred
    Kerns, Edward H.
    Kraemer, Stefanie D.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sugano, Kiyohiko
    Evidence-based approach to assess passive diffusion and carrier-mediated drug transport2012In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 17, no 15-16, p. 905-912Article, review/survey (Refereed)
    Abstract [en]

    Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to passive diffusion. Misconceptions and faulty speculations are addressed to provide reliable guidance on choosing appropriate tools for drug design and optimization.

  • 22.
    Dubbelboer, Ilse R
    et al.
    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.
    Ahnfelt, Emelie
    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, Niklas
    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.
    Treatment of intermediate stage hepatocellular carcinoma: a review of intrahepatic doxorubicin drug-delivery systems2014In: Therapeutic delivery, ISSN 2041-5990, E-ISSN 2041-6008, Vol. 5, no 4, p. 447-466Article in journal (Refereed)
    Abstract [en]

    The biopharmaceutical properties of doxorubicin delivered via two drug-delivery systems (DDSs) for the palliative treatment of unresectable hepatocellular carcinoma were reviewed with relation to the associated liver and tumor (patho)physiology. These two DDSs, doxorubicin emulsified with Lipiodol(®) and doxorubicin loaded into DC Bead(®) are different regarding tumor delivery, release rate, local bioavailability, if and how they can be given repeatedly, biodegradability, length of embolization and safety profile. There have been few direct head-to-head comparisons of these DDSs, and in-depth investigations into their in vitro and in vivo performance is warranted.

  • 23.
    Dubbelboer, Ilse R
    et al.
    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.
    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.
    Piquette-Miller, Micheline
    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 Lipiodol and Cyclosporin A on the Hepatobiliary Disposition of Doxorubicin in Pigs2014In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 4, p. 1301-1313Article in journal (Refereed)
    Abstract [en]

    Doxorubicin (DOX) emulsified in Lipiodol (LIP) is used as local palliative treatment for unresectable intermediate stage hepatocellular carcinoma. The objective of this study was to examine the poorly understood effects of the main excipient in the drug delivery system, LIP, alone or together with cyclosporin A (CsA), on the in vivo liver disposition of DOX. The advanced, multi-sampling-site, acute pig model was used; samples were collected from three blood vessels (v. portae, v. hepatica and v. femoralis), bile and urine. The four treatment groups (TI-TIV) all received two intravenous 5 min infusions of DOX into an ear vein: at 0 and 200 min. Before the second dose, the pigs received a portal vein infusion of saline (TI), LIP (TII), CsA (TIII) or LIP and CsA (TIV). Concentrations of DOX and its active metabolite doxorubicinol (DOXol) were analyzed using UPLC-MS/MS. A multi-compartment model was developed to describe the distribution of DOX and DOXol in plasma, bile and urine. LIP did not affect the pharmacokinetics of DOX or DOXol. CsA (TIII and TIV) had no effect on the plasma pharmacokinetics of DOX, but a 2-fold increase in exposure to DOXol and a significant decrease in hepatobiliary clearance of DOX and DOXol was observed. Model simulations supported that CsA inhibits 99% of canalicular biliary secretion of both DOX and DOXol, but does not affect the metabolism of DOX to DOXol. In conclusion, LIP did not interact with transporters, enzymes and/or biological membranes important for the hepatobiliary disposition of DOX.

  • 24.
    Dubbelboer, Ilse R
    et al.
    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.
    Karalli, Amar
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm.
    Axelsson, Rimma
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm.
    Brismar, Torkel B
    Karolinska Univ Hosp Huddinge, Dept Radiol, Stockholm.; Karolinska Inst, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm.
    Ebeling Barbier, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Norén, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Duraj, Frans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Mikael, Hedeland
    Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala.
    Bondesson, Ulf
    Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Stål, Per
    Karolinska Inst, Dept Internal Med Huddinge, Unit Gastroenterol, Stockholm.; Karolinska Univ Hosp Huddinge, Dept Digest Dis, Stockholm.
    Nyman, Rickard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Reply to "Comment on 'In Vivo Drug Delivery Performance of Lipiodol-Based Emulsion or Drug-Eluting Beads in Patients with Hepatocellular Carcinoma'"2018In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 1, p. 336-340Article in journal (Refereed)
  • 25.
    Dubbelboer, Ilse R.
    et al.
    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.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A Model -Based Approach To Assessing the Importance of Intracellular Binding Sites in Doxorubicin Disposition2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 3, p. 686-698Article in journal (Refereed)
    Abstract [en]

    Doxorubicin is an anticancer agent, which binds reversibly to topoisomerase I and II, intercalates to DNA base pairs, and generates free radicals. Doxorubicin has a high tissue:plasma partition coefficient and high intracellular binding to the nucleus and other subcellular compartments. The metabolite doxorubicinol has an extensive tissue distribution. This porcine study investigated whether the traditional implementation of tissue binding, described by the tissue:plasma partition coefficient (K-p,K-t),could be used to appropriately analyze and/or simulate tissue doxorubicin and doxorubicinol concentrations in healthy pigs, when applying a physiologically based pharmacokinetic (PBPK) model approach, or whether intracellular binding is required in the semi-PBPK model. Two semi-PBPK models were developed and evaluated using doxorubicin and doxorubicinol concentrations in healthy pig blood, bile, and urine and kidney and liver tissues. In the generic semi-PBPK model, tissue binding was described using the conventional K-p,K-t approach. In the binding-specific semi-PBPK model, tissue binding was described using intracellular binding sites. The best semi-PBPK model was validated against a second data set of healthy pig blood and bile concentrations. Both models could be used for analysis and simulations of biliary and urinary excretion of doxorubicin and doxorubicinol and plasma doxorubicinol concentrations in pigs, but the binding-specific model was better at describing plasma doxorubicin concentrations. Porcine tissue concentrations were 400- to 1250-fold better captured by the binding-specific model. This model adequately predicted plasma doxorubicin concentration time and biliary doxorubicin excretion profiles against the validation data set. The semi-PBPK models applied were similarly effective for analysis of plasma concentrations and biliary and urinary excretion of doxorubicin and doxorubicinol in healthy pigs. Inclusion of intracellular binding in the doxorubicin semi-PBPK models was important to accurately describe tissue concentrations during in vivo conditions.

  • 26.
    Dubbelboer, Ilse R
    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.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment2018In: AAPS Journal, ISSN 1550-7416, E-ISSN 1550-7416, Vol. 20, no 6, article id 96Article in journal (Refereed)
    Abstract [en]

    It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. However, mathematical modeling can be used to predict doxorubicin release properties from these formulations and its in vivo pharmacokinetic (PK) profiles. A porcine semi-physiologically based pharmacokinetic (PBPK) model was scaled to a human physiologically based biopharmaceutical (PBBP) model that was altered to include HCC. DOX in vitro and in vivo release data from LIPDOX or DEBDOX were collected from the literature and combined with these in silico models. The simulated pharmacokinetic profiles were then compared with observed porcine and human HCC patient data. DOX pharmacokinetic profiles of LIPDOX-treated HCC patients were best predicted from release data sets acquired by in vitro methods that did not use a diffusion barrier. For the DEBDOX group, the best predictions were from the in vitro release method with a low ion concentration and a reduced loading dose. The in silico modeling combined with historical release data was effective in predicting in vivo plasma exposure. This can give useful insights into the release method properties necessary for correct in vivo predictions of pharmacokinetic profiles of HCC patients dosed with LIPDOX or DEBDOX.

  • 27.
    Eriksson, Johanna
    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.
    Thörn, Helena
    AstraZeneca, Phannaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden..
    Rubin, Katarina
    Bäckman, Per
    AstraZeneca, Phannaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden.;Mylan Pharma UK Ltd, Mylan Global Resp Grp, Sandwich CT13 9FF, Kent, England..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pulmonary absorption - estimation of effective pulmonary permeability and tissue retention of ten drugs using an ex vivo rat model and computational analysis2018In: European journal of pharmaceutics and biopharmaceutics, ISSN 0939-6411, E-ISSN 1873-3441, Vol. 124, p. 1-12Article in journal (Refereed)
    Abstract [en]

    Permeation of inhaled drugs across the pulmonary epithelium can regulate the rate and extent of local drug absorption and hence the pulmonary tissue concentration. Therefore, understanding pulmonary epithelial transport could be important for successful design of novel inhaled medicines. To enhance understanding of pulmonary epithelial transport, drug transport data were generated for a set of inhaled compounds (n = 10) in the single-pass, isolated perfused rat lung model. A compartmental in silica model was used to estimate pulmonary permeability and tissue retention. The theoretical model was also used to re-analyze previously obtained historical drug transport data from the isolated perfused lung (n = 10) with re-circulating buffer. This was performed to evaluate the re-circulating model for assessing tissue retention measurements and to increase the number of data points. The tissue retention was an important parameter to estimate to be able to describe the drug transport profiles accurately of most of the investigated compounds. A relationship between the pulmonary permeability and the intrinsic (carrier-mediated transport inhibited) permeability of Caco-2 cell monolayers (n = 1-6) was also established. This correlation (R-2 = 0.76, p < .0001) suggests that intrinsic Caco-2 permeability measurements could offer early predictions of the passive transcellular permeability of lung epithelium to candidate drugs. Although, for some compounds a deviation from the correlation suggests that other transport mechanisms may coexist. The compartmental in silica model was successful in describing the pulmonary drug transport profiles of the investigated compounds and has potential for further development to investigate the effects of formulations with different features on the pulmonary overall absorption rate.

  • 28.
    Eriksson, Johanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Thorn, Helena
    AstraZeneca, Pharmaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Sjögren, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Holmsten, Lisa
    AstraZeneca, Pharmaceut Technol & Dev Inhalat, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Rubin, Katarina
    AstraZeneca, Innovat Med & Early Dev, Resp Inflammat & Autoimmun, Pepparedsleden 1, S-43183 Molndal, Sweden.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pulmonary Dissolution of Poorly Soluble Compounds Studied in an ex Vivo Rat Lung Model2019In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 16, no 7, p. 3053-3064Article in journal (Refereed)
    Abstract [en]

    Many inhaled drugs are poorly water soluble, and the dissolution rate is often the rate-limiting step in the overall absorption process. To improve understanding of pulmonary drug dissolution, four poorly soluble inhalation compounds (AZD5423 (a developmental nonsteroidal glucocorticoid), budesonide, fluticasone furoate (FF), and fluticasone propionate (FP)) were administered as suspensions or dry powders to the well-established isolated perfused 4 rat lung (IPL) model. Two particle size distributions (d50 = 1.2 mu m and d50 = 2.8 mu m) were investigated for AZD5423. The pulmonary absorption rates of the drugs from the suspensions and dry powders were compared with historical absorption data for solutions to improve understanding of the effects of dissolution on the overall pulmonary absorption process for poorly soluble inhaled drugs. A physiologically based biopharmaceutical in silico model was used to analyze the experimental IPL data and to estimate a dissolution parameter (K-ex vivo). A similar in silico approach was applied to in vitro dissolution data from the literature to obtain an in vitro dissolution parameter (Kin vitro). When FF, FP, and the larger particles of AZD5423 were administered as suspensions, drug dissolution was the rate-limiting step in the overall absorption process. However, this was not the case for budesonide, which has the highest aqueous solubility (61 mu M), and the smaller particles of AZD5423, probably because of the increased surface area available for dissolution (d50 = 1.2 mu m). The estimated dissolution parameters were ranked in accordance with the solubility of the drugs, and there was good agreement between k(ex vivo) and k(in vitro). The dry powders of all the compounds were absorbed more slowly than the suspensions, indicating that wetting is an important parameter for the dissolution of dry powders. A wetting factor was introduced to the in silico model to explain the difference in absorption profiles between the suspensions and dry powders where AZD5423 had the poorest wettability followed by FP and FF. The IPL model in combination with an in silico model is a useful tool for investigating pulmonary dissolution and improving understanding of dissolution-related parameters for poorly soluble inhaled compounds.

  • 29.
    Forner, Kristin
    et al.
    Johannes Gutenberg Univ Mainz, Dept Pharmaceut Technol & Biopharmaceut, Staudingerweg 5, D-55128 Mainz, Germany..
    Roos, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dahlgren, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kesisoglou, Filippos
    Merck & Co Inc, Dept Biopharmaceut Pharmaceut Sci & Clin Supply, Kenilworth, NJ USA..
    Konerding, Moritz A.
    Johannes Gutenberg Univ Mainz, Inst Clin & Funct Anat, Univ Med Ctr, Mainz, Germany..
    Mazur, Johanna
    Johannes Gutenberg Univ Mainz, Inst Med Biostat Epidemiol & Informat, Univ Med Ctr, Mainz, Germany..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Dept Pharmaceut Technol & Biopharmaceut, Staudingerweg 5, D-55128 Mainz, Germany..
    Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs2017In: Drug Development and Industrial Pharmacy, ISSN 0363-9045, E-ISSN 1520-5762, Vol. 43, no 2, p. 338-346Article in journal (Refereed)
    Abstract [en]

    Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments. Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media. Methods: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIFmod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant. Results: Fa/FeSSIFmod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations. Discussion: The compatibility of Fa/FeSSIFmod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo. Conclusion: The optimized setup uses FaSSIF(mod) as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

  • 30.
    Frenning, Göran
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ahnfelt, Emelie
    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.
    Computational fluid dynamics (CFD) studies of a miniaturized dissolution system2017In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 521, no 1-2, p. 274-281Article in journal (Refereed)
    Abstract [en]

    Dissolution testing is an important tool that has applications ranging from fundamental studies of drugrelease mechanisms to quality control of the final product. The rate of release of the drug from the delivery system is known to be affected by hydrodynamics. In this study we used computational fluid dynamics to simulate and investigate the hydrodynamics in a novel miniaturized dissolution method for parenteral formulations. The dissolution method is based on a rotating disc system and uses a rotating sample reservoir which is separated from the remaining dissolution medium by a nylon screen. Sample reservoirs of two sizes were investigated (SR6 and SR8) and the hydrodynamic studies were performed at rotation rates of 100, 200 and 400 rpm. The overall fluid flow was similar for all investigated cases, with a lateral upward spiraling motion and central downward motion in the form of a vortex to and through the screen. The simulations indicated that the exchange of dissolution medium between the sample reservoir and the remaining release medium was rapid for typical screens, for which almost complete mixing would be expected to occur within less than one minute at 400 rpm. The local hydrodynamic conditions in the sample reservoirs depended on their size; SR8 appeared to be relatively more affected than SR6 by the resistance to liquid flow resulting from the screen.

  • 31.
    Garcia, Luna Prieto
    et al.
    AstraZeneca, Sodertalje, Sweden.
    Janzen, David
    AstraZeneca, Sodertalje, Sweden.
    Kanebratt, Kajsa
    AstraZeneca, Sodertalje, Sweden.
    Ericsson, Hans
    AstraZeneca, Sodertalje, Sweden.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundahl, Anna
    AstraZeneca, Sodertalje, Sweden.
    Physiologically based pharmacokinetic model predictions of ivosidenib (AG-120) as a victim and perpetrator of drug–drug interactions2019In: Drug Metabolism and Pharmacokinetics, ISSN 1347-4367, E-ISSN 1880-0920, Vol. 34, no 1, p. S70-S71Article in journal (Other academic)
  • 32.
    Garcia, Luna Prieto
    et al.
    AstraZeneca, IMED Biotech Unit, Drug Metab & Pharmacokinet, Cardiovasc & Metab Dis, Gothenburg, Sweden.
    Janzen, David
    AstraZeneca, IMED Biotech Unit, Drug Metab & Pharmacokinet, Cardiovasc & Metab Dis, Gothenburg, Sweden.
    Kanebratt, Kajsa P.
    AstraZeneca, IMED Biotech Unit, Drug Metab & Pharmacokinet, Cardiovasc & Metab Dis, Gothenburg, Sweden.
    Ericsson, Hans
    AstraZeneca, IMED Biotech Unit, Quantitat Clin Pharmacol, Early Clin Dev, Gothenburg, Sweden.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundahl, Anna
    AstraZeneca, IMED Biotech Unit, Drug Metab & Pharmacokinet, Cardiovasc & Metab Dis, Gothenburg, Sweden.
    Physiologically Based Pharmacokinetic Model of Itraconazole and Two of Its Metabolites to Improve the Predictions and the Mechanistic Understanding of CYP3A4 Drug-Drug Interactions2018In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 46, no 10, p. 1420-1433Article in journal (Refereed)
    Abstract [en]

    Physiologically based pharmacokinetic (PBPK) modeling for itraconazole using a bottom-up approach is challenging, not only due to complex saturable pharmacokinetics (PK) and the presence of three metabolites exhibiting CYP3A4 inhibition, but also because of discrepancies in reported in vitro data. The overall objective of this study is to provide a comprehensive mechanistic PBPK model for itraconazole in order to increase the confidence in its drug-drug interaction (DDI) predictions. To achieve this, key in vitro and in vivo data for itraconazole and its major metabolites were generated. These data were crucial to developing a novel bottom-up PBPK model in Simcyp (Simcyp Ltd., Certara, Sheffield, United Kingdom) for itraconazole and two of its major metabolites: hydroxy-itraconazole (OH-ITZ) and keto-itraconazole (keto-ITZ). Performance of the model was validated using prespecified acceptance criteria against different dosing regimens, formulations for 29 PK, and DDI studies with midazolam and other CYP3A4 substrates. The main outcome is an accurate PBPK model that simultaneously predicts the PK profiles of itraconazole, OH-ITZ, and keto-ITZ. In addition, itraconazole DDIs with midazolam and other CYP3A4 substrates were successfully predicted within a 2-fold error. Prediction precision and bias of DDI expressed as geometric mean fold error were for the area under the concentration-time curve and peak concentration, 1.06 and 0.96, respectively. To conclude, in this paper a comprehensive data set for itraconazole and its metabolites is provided that enables bottom-up mechanism-based PBPK modeling. The presented model is applicable for studying the contribution from the metabolites and allows improved assessments of itraconazole DDI.

  • 33. Hedeland, Mikael
    et al.
    Fredriksson, Elisabeth
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bondesson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Simultaneous quantification of the enantiomers of verapamil and its N-demethylated metabolite in human plasma using liquid chromatography-tandem mass spectrometry2004In: Journal of chromatography. B, ISSN 1570-0232, E-ISSN 1873-376X, Vol. 804, no 2, p. 303-311Article in journal (Refereed)
    Abstract [en]

    A stereoselective bioanalytical method for the simultaneous quantification of the enantiomers of verapamil and its active main metabolite norverapamil in human plasma has been developed and validated. The samples were analysed by liquid chromatography-electrospray-tandem mass spectrometry (LC-ESI-MS/MS) in the Selected Reaction Monitoring (SRM) mode using a deuterated internal standard. The stationary phase used for the chiral separation was a Chiral-AGP. The enantiomers of verapamil were selectively detected from those of norverapamil by the mass spectrometer due to different molecular masses, although there was a chromatographic co-elution. Thus, time-consuming procedures like achiral preseparation or chemical derivatisation could be avoided. Higher detection sensitivity than earlier published methods based on fluorescence detection was obtained, although a mobile phase of high water-content and high flow-rate was introduced into the electrospray interface (85% aqueous ammonium acetate pH 7.4 +15% acetonitrile at 0.6 ml/min). The enantiomers of verapamil and norverapamil could be quantified at levels down to 50 pg and 60 pg/500 microl plasma sample, respectively, with R.S.D. in the range of 3.6-7.8%. The presented method was successfully applied to an in vivo intestinal absorption and bioavailability study in humans, using the Loc-I-Gut method.

  • 34. Hedner, Thomas
    et al.
    Lennernäs, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Ottosson, Pontus
    Proposals on the innovation policy by Ostros--correct diagnosis but wrong treatment2004In: Lakartidningen, ISSN 0023-7205, Vol. 101, no 26-27, p. 2287-8Article in journal (Other scientific)
  • 35.
    Hens, Bart
    et al.
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA.;Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Leuven, Belgium..
    Al-Gousous, Jozef
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Wang, Kai
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Salehi, Niloufar
    Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA..
    Ziff, Robert M.
    Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA.;Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA..
    Tsume, Yasuhiro
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Bermejo, Marival
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA.;Miguel Hernandez Univ, Dept Engn, Pharm Sect, Alicante, Spain..
    Paixao, Paulo
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA.;Univ Lisbon, Fac Pharm, Res Inst Med iMed ULisboa, Lisbon, Portugal..
    Brasseur, James G.
    Penn State Univ, Dept Mech & Nucl Engn, University Pk, PA 16802 USA.;Univ Colorado, Dept Aerosp Engn Sci, Boulder, CO 80309 USA..
    Yu, Alex
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Talattof, Arjang
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Benninghoff, Gail
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Dept Pharmaceut Technol & Biopharmaceut, Mainz, Germany..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hasler, William L.
    Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA..
    Marciani, Luca
    Nottingham Univ Hosp NHS Trust, Nottingham Digest Dis Ctr, Nottingham, England.;Nottingham Univ Hosp NHS Trust, Nottingham Biomed Res Ctr 2NIHR, Nottingham, England.;Univ Nottingham, Nottingham, England..
    Sun, Duxin
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Amidon, Gregory E.
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Dickens, Joseph
    Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA..
    Shedden, Kerby
    Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA..
    Lobenberg, Raimar
    Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB, Canada..
    Amidon, Gordon L.
    Univ Michigan, Coll Pharm, Dept Pharmaceut Sci, 428 Church St, Ann Arbor, MI 48109 USA..
    Summary of the In Vivo Predictive Dissolution (iPD) - Oral Drug Delivery (ODD) Conference 20182018In: DISSOLUTION TECHNOLOGIES, ISSN 1521-298X, Vol. 25, no 2, p. 50-53Article in journal (Other academic)
  • 36.
    Hens, Bart
    et al.
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA;Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, B-3000 Leuven, Belgium.
    Sinko, Patrick D.
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Job, Nicholas
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Dean, Meagan
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Al-Gousous, Jozef
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Salehi, Niloufar
    Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA;Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA.
    Ziff, Robert M.
    Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA;Univ Michigan, Dept Chem Engn, Ann Arbor, MI 48109 USA.
    Tsume, Yasuhiro
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Bermejo, Marival
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA;Miguel Hernandez Univ, Dept Engn, Pharm Sect, Alicante, Spain.
    Paixao, Paulo
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA;Univ Lisbon, Fac Pharm, Res Inst Med iMed ULisboa, Av Prof Gama Pinto, P-1649003 Lisbon, Portugal.
    Brasseur, James G.
    Penn State Univ, Dept Mech & Nucl Engn, University Pk, PA 16802 USA;Univ Colorado, Dept Aerosp Engn Sci, Boulder, CO 80309 USA.
    Yu, Alex
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Talattof, Arjang
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Benninghoff, Gail
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Langguth, Peter
    Johannes Gutenberg Univ Mainz, Dept Pharmaceut Technol & Biopharmaceut, Staudinger Weg 5, D-55099 Mainz, Germany.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hasler, William L.
    Univ Michigan, Div Gastroenterol, Dept Internal Med, Ann Arbor, MI 48109 USA.
    Marciani, Luca
    Nottingham Univ Hosp NHS Trust, Nottingham Digest Dis Ctr, Nottingham NG7 2UH, England;Nottingham Univ Hosp NHS Trust, NIHR Nottingham Biomed Res Ctr, Nottingham NG7 2UH, England;Univ Nottingham, Nottingham NG7 2UH, England.
    Dickens, Joseph
    Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA.
    Shedden, Kerby
    Univ Michigan, Dept Stat, Ann Arbor, MI 48109 USA.
    Sun, Duxin
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Amidon, Gregory E.
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Amidon, Gordon L.
    Univ Michigan, Dept Pharmaceut Sci, Coll Pharm, Ann Arbor, MI 48109 USA.
    Formulation predictive dissolution (fPD) testing to advance oral drug product development: An introduction to the US FDA funded '21st Century BA/BE' project2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 548, no 1, p. 120-127Article, review/survey (Refereed)
    Abstract [en]

    Over the past decade, formulation predictive dissolution (fPD) testing has gained increasing attention. Another mindset is pushed forward where scientists in our field are more confident to explore the in vivo behavior of an oral drug product by performing predictive in vitro dissolution studies. Similarly, there is an increasing interest in the application of modern computational fluid dynamics (CFD) frameworks and high-performance computing platforms to study the local processes underlying absorption within the gastrointestinal (GI) tract. In that way, CFD and computing platforms both can inform future PBPK-based in silico frameworks and determine the GI-motility-driven hydrodynamic impacts that should be incorporated into in vitro dissolution methods for in vivo relevance. Current compendial dissolution methods are not always reliable to predict the in vivo behavior, especially not for biopharmaceutics classification system (BCS) class 2/4 compounds suffering from a low aqueous solubility. Developing a predictive dissolution test will be more reliable, cost-effective and less time-consuming as long as the predictive power of the test is sufficiently strong. There is a need to develop a biorelevant, predictive dissolution method that can be applied by pharmaceutical drug companies to facilitate marketing access for generic and novel drug products. In 2014, Prof. Gordon L. Amidon and his team initiated a far-ranging research program designed to integrate (1) in vivo studies in humans in order to further improve the understanding of the intraluminal processing of oral dosage forms and dissolved drug along the gastrointestinal (GI) tract, (2) advancement of in vitro methodologies that incorporates higher levels of in vivo relevance and (3) computational experiments to study the local processes underlying dissolution, transport and absorption within the intestines performed with a new unique CFD based framework. Of particular importance is revealing the physiological variables determining the variability in in vivo dissolution and GI absorption from person to person in order to address (potential) in vivo BE failures. This paper provides an introduction to this multidisciplinary project, informs the reader about current achievements and outlines future directions.

  • 37. Jesson, Gerald
    et al.
    Brisander, Magnus
    Andersson, Per
    Demirbuker, Mustafa
    Derand, Helene
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Malmsten, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Carbon Dioxide-Mediated Generation of Hybrid Nanoparticles for Improved Bioavailability of Protein Kinase Inhibitors2014In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 31, no 3, p. 694-705Article in journal (Refereed)
    Abstract [en]

    A versatile methodology is demonstrated for improving dissolution kinetics, gastrointestinal (GI) absorption, and bioavailability of protein kinase inhibitors (PKIs). The approach is based on nanoparticle precipitation by sub- or supercritical CO2 together with a matrix-forming polymer, incorporating surfactants either during or after nanoparticle formation. Notably, striking synergistic effects between hybrid PKI/polymer nanoparticles and surfactant added after particle formation is investigated. The hybrid nanoparticles, consisting of amorphous PKI embedded in a polymer matrix (also after 12 months), display dramatically increased release rate of nilotinib in both simulated gastric fluid and simulated intestinal fluid, particularly when surfactants are present on the hybrid nanoparticle surface. Similar results indicated flexibility of the approach regarding polymer identity, drug load, and choice of surfactant. The translation of the increased dissolution rate found in vitro into improved GI absorption and bioavalilability in vivo was demonstrated for male beagle dogs, where a 730% increase in the AUC(0-24h) was observed compared to the benchmark formulation. Finally, the generality of the formulation approach taken was demonstrated for a range of PKIs. Hybrid nanoparticles combined with surfactant represent a promising approach for improving PKI dissolution rate, providing increased GI absorption and bioavailability following oral administration.

  • 38. Johannsson, G.
    et al.
    Nilsson, A. G.
    Bergthorsdottir, R.
    Burman, P.
    Dahlqvist, P.
    Ekman, B.
    Edén Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Olsson, T.
    Ragnarsson, O.
    Ryberg, M.
    Wahlberg, J.
    Biller, B. M. K.
    Monson, J. P.
    Stewart, P. M.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Skrtic, S.
    Improved Cortisol Exposure-Time Profile and Outcome in Patients with Adrenal Insufficiency: A Prospective Randomized Trial of a Novel Hydrocortisone Dual-Release Formulation2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 2, p. 473-481Article in journal (Refereed)
    Abstract [en]

    Context: Patients with treated adrenal insufficiency (AI) have increased morbidity and mortality rate. Our goal was to improve outcome by developing a once-daily (OD) oral hydrocortisone dual-release tablet with a more physiological exposure-time cortisol profile.

    Objective: The aim was to compare pharmacokinetics and metabolic outcome between OD and the same daily dose of thrice-daily (TID) dose of conventional hydrocortisone tablets. Design and Setting: We conducted an open, randomized, two-period, 12-wk crossover multicenter trial with a 24-wk extension at five university hospital centers.

    Patients: The trial enrolled 64 adults with primary AI; 11 had concomitant diabetes mellitus (DM). Intervention: The same daily dose of hydrocortisone was administered as OD dual-release or TID. Main Outcome Measure: We evaluated cortisol pharmacokinetics.

    Results: Compared with conventional TID, OD provided a sustained serum cortisol profile 0-4 h after the morning intake and reduced the late afternoon and the 24-h cortisol exposure. The mean weight (difference = -0.7kg, P = 0.005), systolic blood pressure(difference = -5.5 mm Hg, P = 0.0001) and diastolic blood pressure (difference: -2.3 mm Hg; P = 0.03), and glycated hemoglobin (absolute difference = -0.1%, P = 0.0006) were all reduced after OD compared with TID at 12 wk. Compared with TID, a reduction in glycated hemoglobin by 0.6% was observed in patients with concomitant DM during OD (P = 0.004).

    Conclusion: The OD dual-release tablet provided a more circadian-based serum cortisol profile. Reduced body weight, reduced blood pressure, and improved glucose metabolism were observed during OD treatment. In particular, glucose metabolism improved in patients with concomitant DM.

  • 39. Johannsson, Gudmundur
    et al.
    Falorni, Alberto
    Skrtic, Stanko
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quinkler, Marcus
    Monson, John P.
    Stewart, Paul M.
    Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 82, no 1, p. 2-11Article, review/survey (Refereed)
    Abstract [en]

    Glucocorticoid replacement therapy in patients with adrenal insufficiency (AI), whether primary (Addison's disease) or secondary (due to hypopituitarism), has been established for some 50years. The current standard treatment regimen involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone. Based on previous small-scale studies and clinical perception, life expectancy with conventional glucocorticoid replacement therapy has been considered normal, with a low incidence of adverse events. Data from the past 10-15years, however, have shown that morbidity remains high and life expectancy is reduced. The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events. This is thought to reflect a failure of treatment to replicate the natural circadian rhythm of cortisol release, together with a failure to identify and deliver individualized cortisol exposure and to manage patients adequately when increased doses are required. The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively. This review summarizes the morbidity and mortality seen in patients receiving the current standard of care for AI and suggests areas for improvement in glucocorticoid replacement therapy.

  • 40. Johannsson, Gudmundur
    et al.
    Filipsson, Helena
    Bergthorsdottir, Ragnhildur
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Skrtic, Stanko
    Long-acting hydrocortisone for glucocorticoid replacement therapy2007In: Hormone Research, ISSN 0301-0163, E-ISSN 1423-0046, Vol. 68, no Suppl.5, p. 182-188Article in journal (Refereed)
    Abstract [en]

    Background: Glucocorticoid (GC) deficiency is a consequence of various disorders that are by themselves rare. Because of this low prevalence, the low cost of GC replacement therapy and the belief that existing outcomes are good, there has been little interest in development of new and improved pharmaceutical products for treatment of GC deficiency. However, GC replacement therapy is complex: diurnal variation of endogenous cortisol must be replicated, GC needs may change during times of physical and psychological stress and there is no biomarker of its action that can be used to monitor individual dose response. Current Limitations: Recent data suggest that the outcome of established long-term GC replacement therapy may not be as good as previously believed. Short-acting GCs such as hydrocortisone (HC) and cortisone acetate for replacement therapy require 2 to 3 administrations per day. Developing Alternatives: Drug delivery system technologies are now available that could permit design and manufacture of a formulation that could accommodate once-daily administration of HC. Such a formulation would enable more physiological serum cortisol-time profiles than are possible with currently available formulations. This short review provides some background on GC replacement therapy, along with recent data on the outcome of patient groups with GC insufficiency, and briefly discusses some general principles for a controlled-release ('long-acting') HC formulation.

  • 41.
    Johannsson, Gudmundur
    et al.
    Univ Gothenburg, Dept Endocrinol, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Marelli, Claudio
    Shire Int GmbH, Zug, Switzerland..
    Rockich, Kevin
    Shire PLC, Wayne, PA USA..
    Skrtic, Stanko
    Univ Gothenburg, Dept Endocrinol, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden.;AstraZeneca R&D, Molndal, Sweden..
    Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 175, no 1, p. 85-93Article in journal (Refereed)
    Abstract [en]

    Objective: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure-time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5-20 mg and assess intrasubject variability. Methods: Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20-55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3 x 5), and 20 mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24 h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography-tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration-time profiles. Results: DR-HC 20 mg provided higher than endogenous cortisol plasma concentrations 0-4 h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (C-max) was 82.0 and 178.1 ng/mL, while mean area under the concentration-time curve (AUC)(0-infinity) was 562.8 and 1180.8 h x ng/mL with DR-HC 5 and 20 mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20 mg. All exposure PK parameters were less than dose proportional (slope < 1). PK differences between ethnicities were explained by body weight differences. Conclusions: DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional - an important consideration when managing intercurrent illness in patients with adrenal insufficiency.

  • 42. Johannsson, Gudmundur
    et al.
    Skrtic, Stanko
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quinkler, Marcus
    Stewart, Paul M.
    Improving outcomes in patients with adrenal insufficiency: a review of current and future treatments2014In: Current Medical Research and Opinion, ISSN 0300-7995, E-ISSN 1473-4877, Vol. 30, no 9, p. 1833-1847Article, review/survey (Refereed)
    Abstract [en]

    Introduction: Adrenal insufficiency is a rare but life-threatening disease. Conventional therapy consists of glucocorticoid replacement using hydrocortisone administered two or three times daily. Although such therapy extends life expectancy, mortality is not normalized, and quality of life remains poor. This failure to restore normal health is thought to be due to the inability of conventional glucocorticoid replacement therapy to normalize total cortisol exposure and to respond to the increased need for glucocorticoids during illness and stress. Also, current management regimens do not restore or replicate the intrinsic circadian rhythm of cortisol secretion. Areas covered: This narrative review was based on a PubMed and Medline search of all English-language articles on the safety and efficacy of glucocorticoid replacement therapy in patients with adrenal insufficiency. Based on this search we discuss current treatment strategies in terms of the failure to maintain or normalize metabolism and quality of life in patients with adrenal insufficiency. The rationale for, and technology behind, the development of modified-release preparations of hydrocortisone are described, together with the evidence suggesting that hydrocortisone preparations that mimic the physiological circadian pattern of cortisol release are more effective than conventional glucocorticoid replacement therapies. Conclusions: Modified-release hydrocortisone treatments for patients with adrenal insufficiency more closely mimic the physiological circadian pattern of cortisol secretion than conventional twice or thrice daily treatment. The available evidence suggests that these modified-release preparations should improve metabolic outcomes and quality of life.

  • 43. Kasim, Nehal A
    et al.
    Whitehouse, Marc
    Ramachandran, Chandrasekharan
    Bermejo, Marival
    Lennernäs, Hans
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Hussain, Ajaz S
    Junginger, Hans E
    Stavchansky, Salomon A
    Midha, Kamal K
    Shah, Vinod P
    Amidon, Gordon L
    Molecular properties of WHO essential drugs and provisional biopharmaceutical classification.2004In: Mol Pharm, ISSN 1543-8384, Vol. 1, no 1, p. 85-96Article in journal (Refereed)
  • 44. Lagerquist, C
    et al.
    Beigi, F
    Karlen, A
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Lennernas, H
    Department of Pharmacy.
    Lundahl, P
    Effects of cholesterol and model transmembrane proteins on drugpartitioning into lipid bilayers as analysed by immobilized-liposomechromatography.2001In: J Pharm Pharmacol, Vol. 53, p. 1477-Article in journal (Refereed)
  • 45. Langguth, P
    et al.
    Bermejo, M
    Lennernäs, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Preface.2006In: Eur J Pharm Sci, ISSN 0928-0987, Vol. 29, no 3-4, p. 173-Article in journal (Refereed)
  • 46.
    Lennernas, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Regional intestinal drug permeation: Biopharmaceutics and drug development2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, no SI, p. 333-341Article, review/survey (Refereed)
    Abstract [en]

    Over the last 25 years, profound changes have been seen in both the development and regulation of pharmaceutical dosage forms, due primarily to the extensive use of the biopharmaceutical classification system (BCS) in both academia and industry. The BCS and the FDA scale-up and post-approval change guidelines were both developed during the 1990s and both are currently widely used to claim biowaivers. The development of the BCS and its wide acceptance were important steps in pharmaceutical science that contributed to the more rational development of oral dosage forms. The effective permeation (P-eff) of drugs through the intestine often depends on the combined outcomes of passive diffusion and multiple parallel transport processes. Site-specific jejunal P-eff cannot reflect the permeability of the whole intestinal tract, since this varies along the length of the intestine, but is a useful approximation of the fraction of the oral dose that is absorbed. It appears that drugs with a jejunal P-eff > 1.5 x 10(-4) cm/s will be completely absorbed no matter which transport mechanisms are utilized. In this paper, historical clinical data originating from earlier open, single-pass perfusion studies have been used to calculate the P-eff of different substances from sites in the jejunum and ileum. More exploratory in vivo studies are required in order to obtain reliable data on regional intestinal drug absorption. The development of experimental and theoretical methods of assessing drug absorption from both small intestine and various sites in the colon is encouraged. Some of the existing human in vivo data are discussed in relation to commonly used cell culture models. It is crucial to accurately determine the input parameters, such as the regional intestinal P-eff, as these will form the basis for the expected increase in modeling and simulation of all the processes involved in GI drug absorption, thus facilitating successful pharmaceutical development in the future. It is suggested that it would be feasible to use open, single-pass perfusion studies for the in vivo estimation of regional intestinal TV, but that care should be taken in the study design to optimize the absorption conditions.

  • 47. Lennernäs, B
    et al.
    Hedner, T
    Holmberg, M
    Bredenberg, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Nyström, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Lennernäs, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain.2005In: Br J Clin Pharmacol, ISSN 0306-5251, Vol. 59, no 2, p. 249-53Article in journal (Refereed)
  • 48.
    Lennernäs, H
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Drug transporters: Where is the research taking us?2004In: Eur J Pharm Sci, Vol. 23:S3-S4, Suppl 1Article in journal (Refereed)
  • 49.
    Lennernäs, H
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Intestinal permeability and its relevance for absorption and elimination2007In: Xenobiotica, ISSN 0049-8254, E-ISSN 1366-5928, Vol. 37, no 10-11, p. 1015-1051Article in journal (Refereed)
    Abstract [en]

    Human jejunal permeability (P-eff) is determined in the intestinal region with the highest expression of carrier proteins and largest surface area. Intestinal P-eff are often based on multiple parallel transport processes. Site-specific jejunal P-eff cannot reflect the permeability along the intestinal tract, but they are useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal P-eff > 1. 5 x 10(-4) cm s(-1) will be completely absorbed no matter which transport mechanism(s) are utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal absorption (i.e. > 85%) mediated by passive transcellular diffusion. The determined jejunal P-eff for drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The data also show that: (1) the human intestinal epithelium has a large resistance towards large and hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger than approximately molecular weight 200. There is a need for more exploratory in vivo studies to clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would stimulate the development of more relevant and complex in vitro absorption models and form the basis for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.

  • 50.
    Lennernäs, H
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Abrahamsson, B
    The biopharmaceutical classification system2006In: Comprehensive medicinal chemistry, Elsevier , 2006Chapter in book (Refereed)
123 1 - 50 of 105
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