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  • 1.
    Ahlin, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karlsson, Johan
    Pedersen, Jenny M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gustavsson, Lena
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Bergström, Christel A S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Structural requirements for drug inhibition of the liver specific human organic cation transport protein 12008In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 19, p. 5932-5942Article in journal (Refereed)
    Abstract [en]

    The liver-specific organic cation transport protein (OCT1; SLC22A1) transports several cationic drugs including the antidiabetic drug metformin and the anticancer agents oxaliplatin and imatinib. In this study, we explored the chemical space of registered oral drugs with the aim of studying the inhibition pattern of OCT1 and of developing predictive computational models of OCT1 inhibition. In total, 191 structurally diverse compounds were examined in HEK293-OCT1 cells. The assay identified 47 novel inhibitors and confirmed 15 previously known inhibitors. The enrichment of OCT1 inhibitors was seen in several drug classes including antidepressants. High lipophilicity and a positive net charge were found to be the key physicochemical properties for OCT1 inhibition, whereas a high molecular dipole moment and many hydrogen bonds were negatively correlated to OCT1 inhibition. The data were used to generate OPLS-DA models for OCT1 inhibitors; the final model correctly predicted 82% of the inhibitors and 88% of the noninhibitors of the test set.

  • 2.
    Alhalaweh, Amjad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alzghoul, Ahmad
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Kaialy, Waseem
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Computational predictions of glass-forming ability and crystallization tendency of drug molecules2014In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 11, no 9, p. 3123-3132Article in journal (Refereed)
    Abstract [en]

    Amorphization is an attractive formulation technique for drugs suffering from poor aqueous solubility as a result of their high lattice energy. Computational models that can predict the material properties associated with amorphization, such as glass-forming ability (GFA) and crystallization behavior in the dry state, would be a time-saving, cost-effective, and material-sparing approach compared to traditional experimental procedures. This article presents predictive models of these properties developed using support vector machine (SVM) algorithm. The GFA and crystallization tendency were investigated by melt-quenching 131 drug molecules in situ using differential scanning calorimetry. The SVM algorithm was used to develop computational models based on calculated molecular descriptors. The analyses confirmed the previously suggested cutoff molecular weight (MW) of 300 for glass-formers, and also clarified the extent to which MW can be used to predict the GFA of compounds with MW < 300. The topological equivalent of Grav3_3D, which is related to molecular size and shape, was a better descriptor than MW for GFA; it was able to accurately predict 86% of the data set regardless of MW. The potential for crystallization was predicted using molecular descriptors reflecting Hückel pi atomic charges and the number of hydrogen bond acceptors. The models developed could be used in the early drug development stage to indicate whether amorphization would be a suitable formulation strategy for improving the dissolution and/or apparent solubility of poorly soluble compounds.

  • 3.
    Alhalaweh, Amjad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alzghoul, Ahmad
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Physical stability of drugs after storage above and below the glass transition temperature: Relationship to glass-forming ability2015In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 495, no 1, p. 312-317Article in journal (Refereed)
    Abstract [en]

    Amorphous materials are inherently unstable and tend to crystallize upon storage. In this study, we investigated the extent to which the physical stability and inherent crystallization tendency of drugs are related to their glass-forming ability (GFA), the glass transition temperature (T-g) and thermodynamic factors. Differential scanning calorimetry was used to produce the amorphous state of 52 drugs [ 18 compounds crystallized upon heating (Class II) and 34 remained in the amorphous state (Class III)] and to perform in situ storage for the amorphous material for 12 h at temperatures 20 degrees C above or below the T-g. A computational model based on the support vector machine (SVM) algorithm was developed to predict the structure-property relationships. All drugs maintained their Class when stored at 20 degrees C below the T-g. Fourteen of the Class II compounds crystallized when stored above the T-g whereas all except one of the Class III compounds remained amorphous. These results were only related to the glass-forming ability and no relationship to e. g. thermodynamic factors was found. The experimental data were used for computational modeling and a classification model was developed that correctly predicted the physical stability above the T-g. The use of a large dataset revealed that molecular features related to aromaticity and pi-pi interactions reduce the inherent physical stability of amorphous drugs.

  • 4.
    Alhalaweh, Amjad
    et al.
    Purdue Univ, Dept Ind & Phys Pharm, Coll Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Taylor, Lynne S.
    Purdue Univ, Dept Ind & Phys Pharm, Coll Pharm, 575 Stadium Mall Dr, W Lafayette, IN 47907 USA.
    Compromised in vitro dissolution and membrane transport of multidrug amorphous formulations.2016In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 229, p. 172-182Article in journal (Refereed)
    Abstract [en]

    Herein, the thermodynamic properties of solutions evolving from the non-sink dissolution of amorphous solid dispersions (ASDs) containing two or more drugs have been evaluated, focusing on the maximum achievable supersaturation and tendency of the system to undergo liquid-liquid phase separation (LLPS). Ritonavir (RTV) and atazanavir (ATV) were co-formulated with polyvinylpyrrolidone to produce ASDs with different molar ratios of each drug, and the dissolution profile of each drug was studied under non-sink conditions. The phase behavior of the supersaturated solutions generated by ASD dissolution was compared to that of supersaturated solutions generated by antisolvent addition. Dissolution of an ASD containing RTV, ATV and lopinavir (LPV) was also investigated. A thermodynamic model was used to predict the maximum achievable supersaturation for ASDs containing two and three drugs. In addition, a transport study with Caco-2 cells was conducted to evaluate the impact of co-addition of drugs on membrane transport. It was found that the formulation containing a 1:1 molar ratio of RTV and ATV achieved only 50% of the supersaturation attained by dissolution of the single drug systems. The maximum achievable concentration of ATV decreased linearly as the mole fraction of ATV in the formulation decreased and a similar trend was observed for RTV. For the dispersion containing a 1:1:1 molar ratio of RTV, ATV and LPV, the maximum concentration of each drug was only one third of that achieved for the single drug formulations. The decrease in the achievable supersaturation was well-predicted by the thermodynamic model for both the binary and ternary drug combinations. These observations can be explained by a decrease in the concentration at which the drugs undergo LLPS in the presence of other miscible drugs, thereby reducing the maximum achievable supersaturation of each drug. The reduced free drug concentration was reflected by a decreased flux across Caco-2 cells for the drug combinations compared to drug alone. This study sheds light on the complex dissolution and solution phase behavior of multicomponent amorphous dosage forms, in particular those containing poorly water soluble drugs, which may undergo supersaturation in vivo.

  • 5.
    Alskär, Linda C
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Models for Predicting Drug Absorption From Oral Lipid-Based Formulations2015In: Current molecular biology reports, ISSN 2198-6428, Vol. 1, no 4, p. 141-147Article in journal (Refereed)
    Abstract [en]

    In this review, we describe the in vitro tools currently used to identify when a lipid-based formulation has the potential to deliver a poorly water-soluble drug via the oral route. We describe the extent to which these tools reflect the in vivo performance of the formulation and, more importantly, we present strategies that we foresee will improve the in vitro-in vivo correlations. We also present emerging computational methods that are likely to allow large parts of the formulation development to be carried out in the computer rather than in the test tube. We suggest that these computational tools will also improve the mechanistic understanding of in vivo formulation performance in the complex and dynamic environment of the gut.

  • 6.
    Alskär, Linda C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Keemink, Janneke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johannesson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Porter, Christopher J H
    Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
    Impact of Drug Physicochemical Properties on Lipolysis-Triggered Drug Supersaturation and Precipitation from Lipid-Based Formulations2018In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 10, p. 4733-4744Article in journal (Refereed)
    Abstract [en]

    In this study we investigated lipolysis-triggered supersaturation and precipitation of a set of model compounds formulated in lipid-based formulations (LBFs). The purpose was to explore the relationship between precipitated solid form and inherent physicochemical properties of the drug. Eight drugs were studied after formulation in three LBFs, representing lipid-rich (extensively digestible) to surfactant-rich (less digestible) formulations. In vitro lipolysis of drug-loaded LBFs were conducted, and the amount of dissolved and precipitated drug was quantified. Solid form of the precipitated drug was characterized with polarized light microscopy (PLM) and Raman spectroscopy. A significant solubility increase for the weak bases in the presence of digestion products was observed, in contrast to the neutral and acidic compounds for which the solubility decreased. The fold-increase in solubility was linked to the degree of ionization of the weak bases and thus their attraction to free fatty acids. A high level of supersaturation was needed to cause precipitation. For the weak bases, the dose number indicated that precipitation would not occur during lipolysis; hence, these compounds were not included in further studies. The solid state analysis proved that danazol and griseofulvin precipitated in a crystalline form, while niclosamide precipitated as a hydrate. Felodipine and indomethacin crystals were visible in the PLM, whereas the Raman spectra showed presence of amorphous drug, indicating amorphous precipitation that quickly crystallized. The solid state analysis was combined with literature data to allow analysis of the relationship between solid form and the physicochemical properties of the drug. It was found that low molecular weight and high melting temperature increases the probability of crystalline precipitation, whereas precipitation in an amorphous form was favored by high molecular weight, low melting temperature, and positive charge.

  • 7.
    Alskär, Linda C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Parrow, Albin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Keemink, Janneke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Pernilla, Johansson
    AstraZeneca R&D, Gothenburg, Sweden .
    Abrahamsson, Bertil
    AstraZeneca R&D, Gothenburg, Sweden .
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Effect of Lipids on Absorption of Carvedilol in Dogs: Is Coadministration of Lipids as Efficient as a Lipid-Based Formulation?Manuscript (preprint) (Other academic)
    Abstract [en]

    Lipid-based formulations (LBFs) is a formulation strategy for enabling oral delivery of poorly water-soluble drugs. However, current use of this strategy is limited to a few percent of the marketed products. Reasons for that are linked to the complexity of LBFs, chemical instability of pre-dissolved drug and a limited understanding of the influence of LBF intestinal digestion on drug absorption. The aim of this study was to explore intestinal drug solubilization from a long-chain LBF, and evaluate whether coadministration of LBF is as efficient as a lipid-based drug formulation containing the pre-dissolved model drug carvedilol. Thus, solubility studies of this weak base were performed in simulated intestinal fluid (SIF) and aspirated dog intestinal fluid (DIF). DIF was collected from duodenal stomas after dosing of water and two levels (1 g and 2 g) of LBF. Similarly, the in vitro SIF solubility studies were conducted prior to, and after addition of, undigested or digested LBF. The DIF fluid was further characterized for lipid digestion products (free fatty acid) and bile salt. Subsequently, carvedilol was orally administered to dogs in a lipid-based drug formulation and coadministered with LBF, and drug plasma exposure was assessed. In addition to these studies, in vitro drug absorption from the different formulation approaches were evaluated in a lipolysis-permeation device, and the obtained data was used to evaluate the in vitro in vivo correlation. The results showed elevated concentrations of free fatty acid and bile salt in the DIF when 2 g of LBF was administered, compared to only water. As expected, the SIF and DIF solubility data revealed that carvedilol solubilization increased by the presence of lipids and lipid digestion products. Moreover, coadministration of LBF and drug demonstrated equal plasma exposure to the lipid-based drug formulation. Furthermore, evaluation of in vitro absorption resulted in the same rank order for the LBFs as in the in vivo dog study. In conclusion, this study demonstrated increased intestinal solubilization from a small amount of LBF, caused by lipid digestion products and bile secretion. The outcomes also support the use of coadministration of LBF as a potential dosing regimen in cases where it is beneficial to have the drug in solid form, e.g. due to chemical instability in the lipid vehicle. Finally, the in vitro lipolysis-permeation used herein established IVIVC for carvedilol in the presence of LBFs.       

  • 8.
    Alskär, Linda C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Porter, Christopher J. H.
    Monash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia..
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. UMonash Univ, Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, Parkville, Vic 3052, Australia..
    Tools for Early Prediction of Drug Loading in Lipid-Based Formulations2016In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 13, no 1, p. 251-261Article in journal (Refereed)
    Abstract [en]

    Identification of the usefulness of lipid-based formulations (LBFs) for delivery of poorly water-soluble drugs is at date mainly experimentally based. In this work we used a diverse drug data set, and more than 2,000 solubility measurements to develop experimental and computational tools to predict the loading capacity of LBFs. Computational models were developed to enable in silico prediction of solubility, and hence drug loading capacity, in the LBFs. Drug solubility in mixed mono-, di-, triglycerides (Maisine 35-1 and Capmul MCM EP) correlated (R-2 0.89) as well as the drug solubility in Carbitol and other ethoxylated excipients (PEG400, R-2 0.85; Polysorbate 80, R-2 0.90; Cremophor EL, R-2 0.93). A melting point below 150 degrees C was observed to result in a reasonable solubility in the glycerides. The loading capacity in LBFs was accurately calculated from solubility data in single excipients (R-2 0.91). In silico models, without the demand of experimentally determined solubility, also gave good predictions of the loading capacity in these complex formulations (R-2 0.79). The framework established here gives a better understanding of drug solubility in single excipients and of LBF loading capacity. The large data set studied revealed that experimental screening efforts can be rationalized by solubility measurements in key excipients or from solid state information. For the first time it was shown that loading capacity in complex formulations can be accurately predicted using molecular information extracted from calculated descriptors and thermal properties of the crystalline drug.

  • 9.
    Alzghoul, Ahmad
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computing Science.
    Alhalaweh, Amjad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Experimental and Computational Prediction of Glass Transition Temperature of Drugs2014In: JOURNAL OF CHEMICAL INFORMATION AND MODELING, ISSN 1549-9596, Vol. 54, no 12, p. 3396-3403Article in journal (Refereed)
    Abstract [en]

    Glass transition temperature (T-g) is an important inherent property of an amorphous solid material which is usually determined experimentally. In this study, the relation between T-g and melting temperature (T-m) was evaluated using a data set of 71 structurally diverse druglike compounds. Further, in silico models for prediction of T-g were developed based on calculated molecular descriptors and linear (multilinear regression, partial least-squares, principal component regression) and nonlinear (neural network, support vector regression) modeling techniques. The models based on T-m predicted T-g with an RMSE of 19.5 K for the test set. Among the five computational models developed herein the support vector regression gave the best result with RMSE of 18.7 K for the test set using only four chemical descriptors. Hence, two different models that predict T-g of drug-like molecules with high accuracy were developed. If T-m is available, a simple linear regression can be used to predict T-g. However, the results also suggest that support vector regression and calculated molecular descriptors can predict T-g with equal accuracy, already before compound synthesis.

  • 10.
    Andersson, Sara B. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alvebratt, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Controlled Suspensions Enable Rapid Determinations of Intrinsic Dissolution Rate and Apparent Solubility of Poorly Water-Soluble Compounds2017In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 34, no 9, p. 1805-1816Article in journal (Refereed)
    Abstract [en]

    Purpose: To develop a small-scale set-up to rapidly and accurately determine the intrinsic dissolution rate (IDR) and apparent solubility of poorly water-soluble compounds.

    Methods: The IDR and apparent solubility (S-app) were measured in fasted state simulated intestinal fluid (FaSSIF) for six model compounds using wet-milled controlled suspensions (1.0% (w/w) PVP and 0.2% (w/w) SDS) and the mu DISS Profiler. Particle size distribution was measured using a Zetasizer and the total surface area was calculated making use of the density of the compound. Powder and disc dissolution were performed and compared to the IDR of the controlled suspensions.

    Results: The IDR values obtained from the controlled suspensions were in excellent agreement with IDR from disc measurements. The method used low amount of compound (mu g-scale) and the experiments were completed within a few minutes. The IDR values ranged from 0.2-70.6 mu g/min/cm(2) and the IDR/S-app ratio ranged from 0.015 to 0.23. This ratio was used to indicate particle size sensitivity on intestinal concentrations reached for poorly water-soluble compounds.

    Conclusions: The established method is a new, desirable tool that provides the means for rapid and highly accurate measurements of the IDR and apparent solubility in biorelevant dissolution media. The IDR/S-app is proposed as a measure of particle size sensitivity when significant solubilization may occur.

  • 11.
    Andersson, Sara B. E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alvebratt, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bevernage, Jan
    Janssen Pharmaceut, Pharmaceut Sci, B-2340 Beerse, Belgium.
    Bonneau, Damien
    Sanofi Aventis Rech Dev, Chem & Pharmaceut Anal, F-34184 Montpellier, France.
    da Costa Mathews, Claudia
    Pfizer Ltd, Pharmaceut Sci, Drug Product Design, Sandwich CT13 9NJ, Kent, England.
    Dattani, Rikesh
    AstraZeneca, Prod Dev, Biopharmaceut, Macclesfield SK10 2NA, Cheshire, England.
    Edueng, Khadijah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    He, Yan
    Sanofi, Predev Sci, Waltham, MA 02451 USA.
    Holm, René
    Pharmaceut Sci & CMC Biol, DK-2500 Copenhagen, Denmark; Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Madsen, Cecilie
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Müller, Thomas
    AbbVie Deutschland GmbH & Co KG, Drug Prod Dev, D-67061 Ludwigshafen, Germany.
    Muenster, Uwe
    Bayer Pharma AG, Res Ctr Aprath, Chem & Pharmaceut Dev, D-42096 Wuppertal, Germany.
    Müllertz, Anette
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Ojala, Krista
    Orion Pharma, POB 65, Espoo 02101, Finland.
    Rades, Thomas
    Univ Copenhagen, Fac Hlth & Med Sci, Dept Pharm, DK-2100 Copenhagen, Denmark.
    Sieger, Peter
    Boehringer Ingelheim GmbH & Co KG, Pharmaceut Dev, D-55218 Ingelheim, Germany.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Interlaboratory Validation of Small-Scale Solubility and Dissolution Measurements of Poorly Water-Soluble Drugs2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 9, p. 2864-2872Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the interlaboratory variability in determination of apparent solubility (Sapp) and intrinsic dissolution rate (IDR) using a miniaturized dissolution instrument. Three poorly water-soluble compounds were selected as reference compounds and measured at multiple laboratories using the same experimental protocol. Dissolution was studied in fasted-state simulated intestinal fluid and phosphate buffer (pH 6.5). An additional 6 compounds were used for the development of an IDR measurement guide, which was then validated with 5 compounds. The results clearly showed a need for a standardized protocol including both the experimental assay and the data analysis. Standardization at both these levels decreased the interlaboratory variability. The results also illustrated the difficulties in performing disc IDR on poorly water-soluble drugs because the concentrations reached are typically below the limit of detection. The following guidelines were established: for compounds with Sapp > 1 mg/mL, the disc method is recommended. For compounds with Sapp <100 μg/mL, IDR is recommended to be performed using powder dissolution. Compounds in the interval 100 μg/mL to 1 mg/mL can be analyzed with either of these methods.

  • 12. Aziz, Emad F
    et al.
    Gråsjö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Forsberg, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Soft X-Ray Physics.
    Andersson, Egil
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Soft X-Ray Physics.
    Söderström, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Duda, Laurent
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Zhang, Wenhua
    Yang, Jinglong
    Eisebitt, Stefan
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Luo, Yi
    Nordgren, Joseph
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Materials Science, Surface and Interface Science.
    Eberhardt, Wolfgang
    Rubensson, Jan-Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Photoinduced Formation of N2 Molecules in Ammonium Compounds2007In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 111, no 39, p. 9662-9669Article in journal (Refereed)
    Abstract [en]

    Via fluorescence yield (FY) and resonant inelastic scattering spectroscopy in the soft X-ray range we find that soft X-rays induce formation of N2 molecules in solid NH4Cl and in related compounds. The nitrogen molecules form weak bonds in NH4Cl, so that a substantial fraction of the molecules remains in the sample. From measurements of the FY as a function of exposure and temperature, the rates for the photochemical processes are estimated. At elevated temperatures (363 K), several nitrogen atoms are removed from the sample per incoming photon. At lower temperatures (233 K), the rate is reduced to around 0.02 nitrogen atoms for each incoming photon. Virtually all these atoms form N2 molecules which are bound in the sample. The generality and implications of these results are briefly discussed.

  • 13.
    Bergstrom, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Charman, Susan A.
    Nicolazzo, Joseph A.
    Computational Prediction of CNS Drug Exposure Based on a Novel In Vivo Dataset2012In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 11, p. 3131-3142Article in journal (Refereed)
    Abstract [en]

    To develop a computational model for predicting CNS drug exposure using a novel in vivo dataset. The brain-to-plasma (B:P) ratio of 43 diverse compounds was assessed following intravenous administration to Swiss Outbred mice. B:P ratios were subjected to PLS modeling using calculated molecular descriptors. The obtained results were transferred to a qualitative setting in which compounds predicted to have a B:P ratio > 0.3 were sorted as high CNS exposure compounds and those below this value were sorted as low CNS exposure compounds. The model was challenged with an external test set consisting of 251 compounds for which semi-quantitative values of CNS exposure were available in the literature. The dataset ranged more than 1700-fold in B:P ratio, with 16 and 27 compounds being sorted as low and high CNS exposure drugs, respectively. The model was a one principal component model based on five descriptors reflecting molecular shape, electronegativity, polarisability and charge transfer, and allowed 74% of the compounds in the training set and 76% of the test set to be predicted correctly. A qualitative computational model has been developed which accurately classifies compounds as being high or low CNS exposure drugs based on rapidly calculated molecular descriptors.

  • 14.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Computational models to predict aqueous drug solubility, permeability and intestinal absorption2005In: Expert opinion on drug metabolism & toxicology, Vol. 1, no 4, p. 613-627Article in journal (Refereed)
    Abstract [en]

    In the last decade, poor intestinal absorption of candidate drugs intended for oral administration has been identified as a major bottleneck in drug development. Poor intestinal absorption can often be related to poor aqueous solubility and/or poor permeability across the intestinal wall. Other factors, such as poor stability and the metabolism of the compounds, can also decrease the amount of compound absorbed. In an effort to design compounds with enhanced absorption profile, theoretical predictions of solubility and permeability, among other factors, have gained increased interest, and a large number of papers have been published. In this review, the databases and techniques used for the development of in silico absorption models will be discussed. The focus is on aqueous drug solubility, which has become a major problem in drug development.

  • 15.
    Bergström, Christel A S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Early recognition of absorption challenges of contemporary targets:: key molecular properties and in silico tools2013In: Bulletin Technique Gattefossé, Vol. 106, p. 50-57Article in journal (Other academic)
    Abstract [en]

    Oral route is the preferred option for the administration of small molecules due to convenience and good patient compliance. For absorption to occur, a drug compound needs to be dissolved in the gastrointestinal fluid to permeate the intestinal membrane. In recent times large efforts have been directed towards solubility enhancing strategies due to the poor solubility profile of the current pipeline of pharmaceutical companies. The reasons for the poor solubility, from a molecular perspective, are related to whether the compound has a solid-state limited or solvation limited solubility. Recent studies indicate that rather simple characterization of a molecule, including calculated molecular properties such as lipophilicity, charge, flexibility, planarity and size can provide information of whether the solubility is restricted by the strong crystal lattice or by poor hydration. Early assessment of these properties will allow the processes which limit solubility to be considered during the early formulation discussions, ultimately guiding toward optimal formulation approaches for new chemical entities (NCEs). Recently, it was shown that it is possible to predict, from molecular structure alone, i) the glass-forming ability of molecules (as an indicator of the possibility to manipulate the solid state as a means to increase dissolution rate/apparent solubility) and ii) drug solubility in commonly used pharmaceutical lipids (as an indicator of the possibility of utilizing lipids to increase the dissolved amount NCE delivered to the intestine). Through approaches like these, the future of formulation design will be transformed from experimental screening efforts to predictive science, allowing better understanding of the molecular interactions that result in successful performance in vivo.

  • 16.
    Bergström, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Andersson, Sara B. E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fagerberg, Jonas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ragnarsson, Gert
    Lindahl, Anders
    Is the full potential of the biopharmaceutics classification system reached?2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, p. 224-231Article in journal (Refereed)
    Abstract [en]

    In this paper we analyse how the biopharmaceutics classification system (BCS) has been used to date. A survey of the literature resulted in a compilation of 242 compounds for which BCS classes were reported. Of these, 183 compounds had been reported to belong to one specific BCS class whereas 59 compounds had been assigned to multiple BCS classes in different papers. Interestingly, a majority of the BCS class 2 compounds had fraction absorbed (FA) values >85%, indicating that they were completely absorbed after oral administration. Solubility was computationally predicted at pH 6.8 for BCS class 2 compounds to explore the impact of the pH of the small intestine, where most of the absorption occurs, on the solubility. In addition, the solubilization capacity of lipid aggregates naturally present in the intestine was studied computationally and experimentally for a subset of 12 compounds. It was found that all acidic compounds with FA > 85% were completely dissolved in the pH of the small intestine. Further, lipids at the concentration used in fasted state simulated intestinal fluid (FaSSIF) dissolved the complete dose given of the most lipophilic (logD(6.5) >3) compounds studied. Overall, biorelevant dissolution media (pure buffer of intestinal pH or FaSSIF) identified that for 20 of the 29 BCS class 2 compounds with FA > 85% the complete dose given orally would be dissolved. These results indicate that a more relevant pH restriction for acids and/or dissolution medium with lipids present better forecast solubility-limited absorption in vivo than the presently used BCS solubility criterion. The analysis presented herein further strengthens the discussion on the requirement of more physiologically relevant dissolution media for the in vitro solubility classification performed to reach the full potential of the BCS. (C) 2013 Elsevier B.V. All rights reserved.

  • 17.
    Bergström, Christel A S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rönn, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Sandström, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
    Hepatitis C virus NS3 protease inhibitors: large, flexible molecules of peptide origin show satisfactory permeability across Caco-2 cells2009In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 38, no 5, p. 556-563Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate the intestinal absorption of tripeptide-based compounds intended for treatment of hepatitis C virus (HCV) infection. The intestinal permeability of 11 HCV NS3 protease inhibitors (Mw 687-841, ClogD(pH 7.4) 1.2-7.3 and 10-13 hydrogen bond donors/acceptors) was measured using Caco-2 cells. Each compound was investigated in the apical to basolateral (a-b) and basolateral to apical (b-a) direction at pH 7.4. For compounds displaying efflux the experiment was repeated in the presence of 1 microM GF120918 to investigate possible involvement of P-glycoprotein (Pgp; ABCB1). All compounds displayed intermediate to high permeability. Seven of them showed extensive efflux, with 31-114-fold higher permeability in the b-a direction than the a-b direction. Addition of the Pgp inhibitor GF120918 reduced the b-a transport rate for the effluxed compounds. However, for inhibitors with a C-terminal carboxylic acid and the acidic bioisosteres thereof the efflux was still significant. Hence, the negative charge resulted in efflux by other ABC-transporters than Pgp. From this study it can be concluded that small changes in the overall structure can lead to a large variation in permeability and efflux as shown by the inhibitors herein, properties that also may influence the resulting inhibition potency of the compounds when performing cell-based pharmacological assays.

  • 18.
    Bergström, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Charman, William N
    Porter, Christopher J H
    Computational prediction of formulation strategies for beyond-rule-of-5 compounds2016In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 101, p. 6-21Article, review/survey (Refereed)
    Abstract [en]

    The physicochemical properties of some contemporary drug candidates are moving towards higher molecular weight, and coincidentally also higher lipophilicity in the quest for biological selectivity and specificity. These physicochemical properties move the compounds towards beyond rule-of-5 (B-r-o-5) chemical space and often result in lower water solubility. For such B-r-o-5 compounds non-traditional delivery strategies (i.e. those other than conventional tablet and capsule formulations) typically are required to achieve adequate exposure after oral administration. In this review, we present the current status of computational tools for prediction of intestinal drug absorption, models for prediction of the most suitable formulation strategies for B-r-o-5 compounds and models to obtain an enhanced understanding of the interplay between drug, formulation and physiological environment. In silico models are able to identify the likely molecular basis for low solubility in physiologically relevant fluids such as gastric and intestinal fluids. With this baseline information, a formulation scientist can, at an early stage, evaluate different orally administered, enabling formulation strategies. Recent computational models have emerged that predict glass-forming ability and crystallisation tendency and therefore the potential utility of amorphous solid dispersion formulations. Further, computational models of loading capacity in lipids, and therefore the potential for formulation as a lipid-based formulation, are now available. Whilst such tools are useful for rapid identification of suitable formulation strategies, they do not reveal drug localisation and molecular interaction patterns between drug and excipients. For the latter, Molecular Dynamics simulations provide an insight into the interplay between drug, formulation and intestinal fluid. These different computational approaches are reviewed. Additionally, we analyse the molecular requirements of different targets, since these can provide an early signal that enabling formulation strategies will be required. Based on the analysis we conclude that computational biopharmaceutical profiling can be used to identify where non-conventional gateways, such as prediction of 'formulate-ability' during lead optimisation and early development stages, are important and may ultimately increase the number of orally tractable contemporary targets.

  • 19.
    Bergström, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Holm, Rene
    Jorgensen, Soren Astrup
    Andersson, Sara B. E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Beato, Stefania
    Borde, Anders
    Box, Karl
    Brewster, Marcus
    Dressman, Jennifer
    Feng, Kung-I.
    Halbert, Gavin
    Kostewicz, Edmund
    McAllister, Mark
    Muenster, Uwe
    Thinnes, Julian
    Taylor, Robert
    Mullertz, Anette
    Early pharmaceutical profiling to predict oral drug absorption: Current status and unmet needs2014In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 57, p. 173-199Article in journal (Refereed)
    Abstract [en]

    Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silica and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered. (C) 2013 Elsevier B.V. All rights reserved.

  • 20.
    Bergström, Christel A S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Larsson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Computational prediction of drug solubility in water-based systems: qualitative and quantitative approaches used in the current drug discovery and development setting2018In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 540, no 1-2, p. 185-193Article, review/survey (Refereed)
    Abstract [en]

    In this review we will discuss recent advances in computational prediction of solubility in water-based solvents. Our focus is set on recent advances in predictions of biorelevant solubility in media mimicking the human intestinal fluids and on new methods to predict the thermodynamic cycle rather than prediction of solubility in pure water through quantitative structure property relationships (QSPR). While the literature is rich in QSPR models for both solubility and melting point, a physicochemical property strongly linked to the solubility, recent advances in the modelling of these properties make use of theory and computational simulations to better predict these properties or processes involved therein (e.g. solid state crystal lattice packing, dissociation of molecules from the lattice and solvation). This review serves to provide an update on these new approaches and how they can be used to more accurately predict solubility, and also importantly, inform us on molecular interactions and processes occurring during drug dissolution and solubilisation.

  • 21.
    Bergström, Christel A. S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Monash Univ, Drug Delivery Disposit & Dynam, Monash Inst Pharmaceut Sci, 381 Royal Parade, Parkville, Vic 3052, Australia..
    Porter, Christopher J. H.
    Monash Univ, Drug Delivery Disposit & Dynam, Monash Inst Pharmaceut Sci, 381 Royal Parade, Parkville, Vic 3052, Australia.;Monash Univ, ARC Ctr Excellence Convergent Nanobio Sci & Techn, Monash Inst Pharmaceut Sci, 381 Royal Parade, Parkville, Vic 3052, Australia..
    Understanding the Challenge of Beyond-Rule-of-5 Compounds Preface2016In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 101, p. 1-5Article in journal (Other academic)
  • 22.
    Bergström, Christel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Haeberlein, Markus
    AstraZeneca R&D Södertälje.
    Norinder, Ulf
    AstraZeneca R&D Södertälje.
    Computational absorption prediction2008In: Drug bioavailability: Estimation of solubility, permeability, absorption and bioavailability / [ed] Han van de Waterbeemd, Bernard Testa, Wernheim: Wiley-VCH , 2008, 2., completely revised edition, p. 409-432Chapter in book (Other academic)
  • 23.
    Bergström, Christel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wassvik, Carola M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Johansson, Kajsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hubatsch, Ina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Poorly soluble marketed drugs display solvation limited solubility2007In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 50, no 23, p. 5858-5862Article in journal (Refereed)
    Abstract [en]

    We determined the intrinsic aqueous solubility of 15 poorly soluble drugs with solubilities ranging from 2.9 nM to 1.1 μM. We then analyzed the data from a physicochemical perspective, using experimentally determined solid-state properties and easily interpretable two-dimensional molecular descriptors, to better understand the factors underlying poor solubility. The analysis shows that poorly soluble drugs that have reached the market are solubility limited by solvation rather than by their solid state.

  • 24.
    Clulow, Andrew J.
    et al.
    Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, 381 Royal Parade, Parkville, Vic 3052, Australia..
    Parrow, Albin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hawley, Adrian
    ANSTO, Australian Synchrotron, 800 Blackburn Rd, Clayton, Vic 3168, Australia..
    Khan, Jamal
    Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, 381 Royal Parade, Parkville, Vic 3052, Australia..
    Pham, Anna C.
    Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, 381 Royal Parade, Parkville, Vic 3052, Australia..
    Larsson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Boyd, Ben J.
    Monash Inst Pharmaceut Sci, Drug Delivery Disposit & Dynam, 381 Royal Parade, Parkville, Vic 3052, Australia..
    Characterization of Solubilizing Nanoaggregates Present in Different Versions of Simulated Intestinal Fluid2017In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 121, no 48, p. 10869-10881Article in journal (Refereed)
    Abstract [en]

    The absorption of hydrophobic drugs and nutrients from the intestine is principally determined by the amount that can be dissolved by the endogenous fluids present in the gut. Human intestinal fluids (HIFs) comprise a complex mixture of bile salts, phospholipids, steroids and glycerides that vary in composition in the fed and fasted state and between subjects. A number of simulated intestinal fluid (SIF) compositions have been developed to mimic fasted and fed state intestinal conditions and allow the in vitro determination of drug solubility as a proxy for the maximum dissolved concentration it is possible to reach. In particular these solvents are used during the development of lipophilic and poorly water-soluble drugs but questions remain around the differences that may arise from the source and methods of preparation of these fluids. In this work, a range of SIFs were studied using small angle X-ray scattering (SAXS), cryogenic -transmission electron microscopy (cryo-TEM) and molecular dynamics (MD) simulations in order to analyze their structures. In-house prepared SIFs based on sodium taurodeoxycholate (NaTDC) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) formed oblate ellipsoidal micelles irrespective of lipid concentration and preparation conditions. In contrast, commercially available SIFs based on sodium taurocholate and lecithin formed prolate ellipsoidal micelles in the fed state and vesicles in the fasted state. These structural variations are the likely reason for the dramatic differences sometimes observed in the solubility enhancements for hydrophobic drugs, nutrients and digestion products when using different SIFs. However, the structural homogeneity of the NaTDC/DOPC micelles makes them ideal candidates for standardizing SIF formulations as the structures of the solubilizing nanoaggregates therein are not sensitive to the preparation method.

  • 25.
    Edueng, Khadijah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Kulliyyah of Pharmacy, International Islamic University Malaysia, Bandar Indera Mahkota, Malaysia.
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    The Need for Restructuring the Disordered Science of Amorphous Drug Formulations2017In: Pharmaceutical Research, ISSN 0724-8741, Vol. 34, no 9, p. 1754-1772Article, review/survey (Refereed)
    Abstract [en]

    The alarming numbers of poorly soluble discovery compounds have centered the efforts towards finding strategies to improve the solubility. One of the attractive approaches to enhance solubility is via amorphization despite the stability issue associated with it. Although the number of amorphous-based research reports has increased tremendously after year 2000, little is known on the current research practice in designing amorphous formulation and how it has changed after the concept of solid dispersion was first introduced decades ago. In this review we try to answer the following questions: What model compounds and excipients have been used in amorphous-based research? How were these two components selected and prepared? What methods have been used to assess the performance of amorphous formulation? What methodology have evolved and/or been standardized since amorphous-based formulation was first introduced and to what extent have we embraced on new methods? Is the extent of research mirrored in the number of marketed amorphous drug products? We have summarized the history and evolution of amorphous formulation and discuss the current status of amorphous formulation-related research practice. We also explore the potential uses of old experimental methods and how they can be used in tandem with computational tools in designing amorphous formulation more efficiently than the traditional trial-and-error approach.

  • 26.
    Edueng, Khadijah
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Int Islamic Univ Malaysia, Kulliyyah Pharm, Jalan Istana, Kuantan 25200, Pahang, Malaysia..
    Mahlin, Denny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Larsson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways2017In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 256, p. 193-202Article in journal (Refereed)
    Abstract [en]

    We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (mu DISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%-0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.

  • 27.
    Fagerberg, Jonas H.
    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.
    Ragnarsson, Gert
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ethanol Effects on Apparent Solubility of Poorly Soluble Drugs in Simulated Intestinal Fluid2012In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 9, no 7, p. 1942-1952Article in journal (Refereed)
    Abstract [en]

    Ethanol intake can lead to an unexpected and possibly problematic increase in the bioavailability of druglike compounds. In this work we investigated the effect of ethanol on the apparent solubility and dissolution rate of poorly soluble compounds in simulated intestinal fluid representing a preprandial state. A series of 22 structurally diverse, poorly soluble compounds were measured for apparent solubility and intrinsic dissolution rate (37 degrees C) in phosphate buffer pH 6.5 (PhB6.5) and fasted state simulated intestinal fluid (FaSSIF, pH 6.5) with and without ethanol at 5% v/v or 20% v/v. The obtained data were used to understand for which molecules ethanol results in an increased apparent solubility and, therefore, may increase the amount of drug absorbed. In FaSSIF(20%ethanol) 59% of the compounds displayed >3-fold higher apparent solubility than in pure FaSSIF, whereas the effects of 5% ethanol on solubility, in most cases, were negligible. Acidic and neutral compounds were more solubilized by the addition of ethanol than by lecithin/taurocholate aggregates, whereas bases showed a more substance-specific response to the additives in the buffer. The stronger solubilizing capacity of ethanol as compared to the mixed lipid aggregates in FaSSIF was further identified through Spearman rank analyses, which showed a stronger relationship between FaSSIF(20%ethanol) and PhB6.5,20%ethanol (r(S) of 0.97) than FaSSIF(20%ethanol) and FaSSIF (r(S) of 0.86). No relationships were found between solubility changes in media containing ethanol and single physicochemical properties, but multivariate data analysis showed that inclusion of ethanol significantly reduced the negative effect of compound lipophilicity on solubility. For this data set the higher concentration of ethanol gave a dose number (Do) <1 for 30% of the compounds that showed incomplete dissolution in FaSSIF. Significant differences were shown in the melting point, lipophilicity, and dose profiles between the compounds having a Do < 1 and Do > 1, with the latter having higher absolute values in all three parameters. In conclusion, this study showed that significant effects of ethanol on apparent solubility in the preprandial state can be expected for lipophilic compounds. The results herein indicate that acidic and neutral compounds are more sensitive to the addition of ethanol than to the mixed lipid aggregates present in the fasted intestine.

  • 28.
    Fagerberg, Jonas H
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Intestinal solubility and absorption of poorly water soluble compounds: predictions, challenges and solutions2015In: Therapeutic delivery, ISSN 2041-5990, E-ISSN 2041-6008, Vol. 6, no 8, p. 935-959Article, review/survey (Refereed)
    Abstract [en]

    We have explored for which type of compounds biorelevant dissolution profiling in simulated intestinal fluids would accurately predict solubility in human intestinal fluid. In total, 460 solubility values in simulated and aspirated human intestinal fluid for 78 drugs were compiled and analyzed. Significant solubilization in the colloidal structures was obtained in fasted and fed state fluids for drug compounds with a logD(oct)>3. Highly lipophilic compounds with high melting points (Tm > 200 °C) could also be significantly solubilized, but typically such compounds had solubility values in the lower µg/ml range also in the presence of the colloidal structures. On the basis of our analysis, compounds with a logD(oct)>3 should be explored in biorelevant dissolution media to better predict in vivo performance after oral dosing.

  • 29.
    Fagerberg, Jonas H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karlsson, Eva
    Ulander, Johan
    Hanisch, Gunilla
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Computational Prediction of Drug Solubility in Fasted Simulated and Aspirated Human Intestinal Fluid2015In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 32, no 2, p. 578-589Article in journal (Refereed)
    Abstract [en]

    Purpose

    To develop predictive models of apparent solubility (Sapp) of lipophilic drugs in fasted state simulated intestinal fluid (FaSSIF) and aspirated human intestinal fluid (HIF).

    Methods

    Measured Sapp values in FaSSIF, HIF and phosphate buffer pH 6.5 (PhBpH6.5) for 86 lipophilic drugs were compiled and divided into training (Tr) and test (Te) sets. Projection to latent structure (PLS) models were developed through variable selection of calculated molecular descriptors. Experimentally determined properties were included to investigate their contribution to the predictions.

    Results

    Modest relationships between Sapp in PhBpH6.5 and FaSSIF (R2 = 0.61) or HIF (R2 = 0.62) were found. As expected, there was a stronger correlation obtained between FaSSIF and HIF (R2 = 0.78). Computational models were developed using calculated descriptors alone (FaSSIF, R2 = 0.69 and RMSEte of 0.77; HIF, R2 = 0.84 and RMSEte of 0.81). Accuracy improved when solubility in PhBpH6.5 was added as a descriptor (FaSSIF, R2 = 0.76 and RMSETe of 0.65; HIF, R2 = 0.86 and RMSETe of 0.69), whereas no improvement was seen when melting point (Tm) or logDpH 6.5 were included in the models.

    Conclusion

    Computational models were developed, that reliably predicted Sapp of lipophilic compounds in intestinal fluid, from molecular structures alone. If experimentally determined pH-dependent solubility values were available, this further improved the accuracy of the predictions.

  • 30.
    Fagerberg, Jonas H.
    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.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Concomitant intake of alcohol may increase the absorption of poorly soluble drugs2015In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 67, p. 12-20Article in journal (Refereed)
  • 31.
    Fagerberg, Jonas H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Tsinman, Oksana
    Sun, Na
    Tsinman, Konstantin
    Avdeef, Alex
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Dissolution Rate and Apparent Solubility of Poorly Soluble Drugs in Biorelevant Dissolution Media2010In: Molecular pharmaceutics, ISSN 1543-8384, Vol. 7, no 5, p. 1419-1430Article in journal (Refereed)
    Abstract [en]

    A series of poorly soluble BCS class II compounds with "grease ball" characteristics were assessed for solubility and dissolution rate in biorelevant dissolution media (BDM) with the purpose of investigating which molecular structures gain most in solubility when dissolved under physiologically relevant conditions. The compounds were studied in four media (simulated intestinal fluid in fasted (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0), and their corresponding blank buffers (FaSSIF(blk) and FeSSIFblk)) at a temperature of 37 degrees C. The experimental results were used to analyze which molecular characteristics are of importance for the solubility in BDM and for in silico modeling using multivariate data analysis. It was revealed that a majority of the compounds exhibited a higher dissolution rate and higher solubility in the FaSSIF and FeSSIF than in their corresponding blank buffers. Compounds which were neutral or carried a positive charge were more soluble in FeSSIF than FaSSIF. The acidic compounds displayed clear pH dependency, although the higher concentration of solubilizing agents in FeSSIF than FaSSIF also improved the solubility. Five of the ten compounds were upgraded to BCS class I when dissolved in FaSSIF or FeSSIF, i.e., the maximum dose of these compounds given orally was soluble in 250 mL of these BDMs. Lipophilicity as described by the log D-oct value was identified as a good predictor of the solubilization ratio (R-2 = 0.74), and computed molecular descriptors were also shown to successfully predict the solubilities in BDM for this data set. To conclude, the physiological solubility of "grease ball" molecules may be largely underestimated in in vitro solubility assays unless BDM is used. Moreover, the results herein indicate that the improvement obtained in BDM may be possible to predict from chemical features alone.

  • 32. Feeney, Orlagh M
    et al.
    Crum, Matthew F
    McEvoy, Claire L
    Trevaskis, Natalie L
    Williams, Hywel D
    Pouton, Colin W
    Charman, William N
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Porter, Christopher J H
    50 years of oral lipid-based formulations: Provenance, progress and future perspectives2016In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 101, p. 167-194Article, review/survey (Refereed)
    Abstract [en]

    Lipid based formulations (LBF) provide well proven opportunities to enhance the oral absorption of drugs and drug candidates that sit close to, or beyond, the boundaries of Lipinski's 'rule-of-five' chemical space. Advantages in permeability, efflux and pre-systemic metabolism are evident; however, the primary benefit is in increases in dissolution and apparent intestinal solubility for lipophilic, poorly water soluble drugs. This review firstly details the inherent advantages of LBF, their general properties and classification and provides a brief retrospective assessment of the development of LBF over the past fifty years. More detailed analysis of the ability of LBF to promote intestinal solubilisation, supersaturation and absorption is then provided alongside review of the methods employed to assess formulation performance. Critical review of the ability of simple dispersion and more complex in vitro digestion methods to predict formulation performance subsequently reveals marked differences in the correlative ability of in vitro tests, depending on the properties of the drug involved. Notably, for highly permeable low melting drugs e.g. fenofibrate, LBF appear to provide significant benefit in all cases, and sustained on-going solubilisation may not be required. In other cases, and particularly for higher melting point drugs such as danazol, where re-dissolution of crystalline precipitate drug is likely to be slow, correlations with on-going solubilisation and supersaturation are more evident. In spite of their potential benefits, one limitation to broader use of LBF is low drug solubility in the excipients employed to generate formulations. Techniques to increase drug lipophilicity and lipid solubility are therefore explored, and in particular those methods that provide for temporary enhancement including lipophilic ionic liquid and prodrug technologies. The transient nature of these lipophilicity increases enhances lipid solubility and LBF viability, but precludes enduring effects on receptor promiscuity and off target toxicity. Finally, recent efforts to generate solid LBF are briefly described as a means to circumvent the need to encapsulate in soft or hard gelatin capsules, although the latter remain popular with consumers and a proven means of LBF delivery.

  • 33. Ferrins, Lori
    et al.
    Gazdik, Michelle
    Rahmani, Raphael
    Varghese, Swapna
    Sykes, Melissa L.
    Jones, Amy J.
    Avery, Vicky M.
    White, Karen L.
    Ryan, Eileen
    Charman, Susan A.
    Kaiser, Marcel
    Bergstroem, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Baell, Jonathan B.
    Pyridyl Benzamides as a Novel Class of Potent Inhibitors for the Kinetoplastid Trypanosoma brucei2014In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 15, p. 6393-6402Article in journal (Refereed)
    Abstract [en]

    A whole-organism screen of approximately 87000 compounds against Trypanosoma brucei brucei identified a number of promising compounds for medicinal chemistry optimization. One of these classes of compounds we termed the pyridyl benzamides. While the initial hit had an IC50 of 12 mu M, it was small enough to be attractive for further optimization, and we utilized three parallel approaches to develop the structure-activity relationships. We determined that the physicochemical properties for this class are generally favorable with particular positions identified that appear to block metabolism when substituted and others that modulate solubility. Our most active compound is 79, which has an IC50 of 0.045 mu M against the human pathogenic strain Trypanosoma brucei rhodesiense and is more than 4000 times less active against the mammalian L6 cell line.

  • 34.
    Gautschi, Nicolas
    et al.
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, Grundenstr 40, CH-4132 Muttenz, Switzerland..
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kuentz, Martin
    Univ Appl Sci & Arts Northwestern Switzerland, Inst Pharmaceut Technol, Grundenstr 40, CH-4132 Muttenz, Switzerland..
    Rapid determination of drug solubilization versus supersaturation in natural and digested lipids2016In: International Journal of Pharmaceutics, ISSN 0378-5173, E-ISSN 1873-3476, Vol. 513, no 1-2, p. 164-174Article in journal (Refereed)
    Abstract [en]

    Lipid-based formulations (LBFs) represent one of the successful formulation approaches that enable oral delivery of poorly water-soluble drugs. This work presents a simple equilibrium approach based on solubility in lipids and their corresponding digestion media to estimate a maximum drug supersaturation ratio (SRmax). This value of drug concentration normalized by the solubility in the aqueous digestion phase indicates the propensity for drug precipitation. A set of 16 structurally diverse drugs was first measured for their solubility in tricaprin and tricaprylin and results were compared to an empirical model based on molecular predictors. In the next step, digestion media were either prepared by in vitro lipolysis or by assembling a composition to mimic the endpoint of digestion. It was found that drug solubility in the pure lipids mainly was related to the melting point in that increased values resulted in reduced solubility. The solubility values measured in the lipolysis media correlated well with those obtained from assembled digestion media. Interestingly, the solubilization upon digestion was typically higher when using tricaprin than tricaprylin in spite of that the latter oil (as pure excipient) generally was a more potent solvent. This work suggests that a simplified digestion screen can be used to facilitate evaluation of formulations during early development. Estimation of SRmax provides an early risk assessment of drug precipitation for LBFs. The method is easily scaled down to the microtiter plate format and can be used for selecting candidate formulations that merit further evaluation in more complex and dynamic in vitro tests.

  • 35.
    Karlgren, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ahlin, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Palm, Johan
    AstraZeneca R&D, Mölndal, Sweden.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In Vitro and In Silico Strategies to Identify OATP1B1 Inhibitors and Predict Clinical Drug-Drug Interactions2012In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 29, no 2, p. 411-426Article in journal (Other academic)
    Abstract [en]

    To establish in vitro and in silico models that predict clinical drug-drug interactions (DDIs) with the OATP1B1 (SLCO1B1) transporter. The inhibitory effect of 146 drugs and drug-like compounds on OATP1B1-mediated transport was studied in HEK293 cells. A computational model was developed to predict OATP1B1 inhibition. Concentration-dependent effects were investigated for six compounds; clinical DDIs were predicted by calculating change in exposure (i.e. R-values) in eight different ways. Sixty-five compounds were identified as OATP1B1 inhibitors at 20 mu M. The computational model predicted the test set with 80% accuracy for inhibitors and 91% for non-inhibitors. In vitro-in vivo comparisons underscored the importance of using drugs with known clinical effects as references. Thus, reference drugs, cyclosporin A, gemfibrozil, and fenofibrate, provided an inhibition interval to which three antiviral drugs, atazanavir, lopinavir, and amprenavir, could be compared and their clinical DDIs with OATP1B1 classified. Twenty-two new OATP1B1 inhibitors were identified, a predictive OATP1B1 inhibition in silico model was developed, and successful predictions of clinical DDIs were obtained with OATP1B1.

  • 36.
    Karlgren, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    How Physicochemical Properties of Drugs Affect Their Metabolism and Clearance2016In: New Horizons in Predictive Drug Metabolism and Pharmacokinetics / [ed] Alan G. E. Wilson, Cambridge: Royal Society of Chemistry, 2016, p. 1-26Chapter in book (Refereed)
    Abstract [en]

    In this chapter the transport proteins and enzymes of importance for drug clearance are discussed. The primary organ for drug metabolism is the liver and to reach the intracellular compartment of hepatocytes, orally administered drugs must cross both the intestinal wall and the cell membrane of the liver cells. Transport proteins present in the cellular membrane may facilitate or hinder the compounds crossing these cellular barriers and hence will influence to what extent compounds will reach the enzymes. Here, the enzymes and transport proteins of importance for drug clearance are discussed. The molecular features of importance for drug interactions with transport proteins and enzymes are analyzed and the possibility to predict molecular features vulnerable to enzymatic degradation is discussed. From detailed analysis of the current literature it is concluded that for interaction, both with transport proteins and enzymes, lipophilicity plays a major role. In addition to this property, molecular properties such as hydrogen bond acceptors and donors, charge, aromaticity and molecular size can be used to distinguish between routes of clearance.

  • 37.
    Keemink, Janneke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Caco-2 Cell Conditions Enabling Studies of Drug Absorptionfrom Digestible Lipid-Based Formulations2018In: Pharmaceutical research, ISSN 0724-8741, E-ISSN 1573-904X, Vol. 35, no 4, article id 74Article in journal (Refereed)
    Abstract [en]

    Purpose To identify conditions allowing the use of cell-based models for studies of drug absorption during in vitro lipolysis of lipid-based formulations (LBFs). Methods Caco-2 was selected as the cell-based model system. Monolayer integrity was evaluated by measuring mannitol permeability after incubating Caco-2 cells in the presence of components available during lipolysis. Pure excipients and formulations representing the lipid formulation classification system (LFCS) were evaluated before and after digestion. Porcine mucin was evaluated for its capacity to protect the cell monolayer. Results Most undigested formulations were compatible with the cells (II-LC, IIIB-LC, and IV) although some needed mucin to protect against damaging effects (II-MC, IIIB-MC, LC, and IIIA-LC). The pancreatic extract commonly used in digestion studies was incompatible with the cells but the Caco-2 monolayers could withstand immobilized recombinant lipase. Upon digestion, long chain formulations caused more damage to Caco-2 cells than their undigested counterparts whereas medium chain formulations showed better tolerability after digestion. Conclusions Most LBFs and components thereof (undigested and digested) are compatible with Caco-2 cells. Pancreatic enzyme is not tolerated by the cells but immobilized lipase can be used in combination with the cell monolayer. Mucin is beneficial for critical formulations and digestion products.

  • 38.
    Larsson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Alskär, Linda C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Molecular Structuring and Phase Transition of Lipid-Based Formulations upon Water Dispersion: A Coarse-Grained Molecular Dynamics Simulation Approach2017In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4145-4153Article in journal (Refereed)
    Abstract [en]

    The internal molecular structure of lipid-based formulations (LBFs) is poorly understood. In this work we aimed at establishing coarse-grained molecular dynamics simulations as a tool for rapid screening and investigation of the internal environment of these formulations. In order to study complex LBFs composed of different kinds of lipids we simulated a number of systems containing either medium-chain or long-chain lipids with varying proportions of tri-, di-, and monoglycerides. Structural and dynamic measurements and analyses identified that the internal environment in a mixture of lipids was locally ordered even in the absence of water, which might explain some of the previously reported effects on drug solubility in these systems. Further, phase changes occurring upon water dispersion are well captured with coarse-grained simulations. Based on these simulations we conclude that the coarse-grained methodology is a promising in silico approach for rapid screening of structures formed in complex formulations. More importantly it facilitates molecular understanding of interactions between excipients and water at a feasible time scale and, hence, opens up for future virtual drug formulation studies.

  • 39.
    Lazorova, Lucia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hubatsch, Ina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ekegren, Jenny K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Gising, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Nakai, Daisuke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Zaki, Noha M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Larhed, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Structural Features Determining the Intestinal Epithelial Permeability and Efflux of Novel HIV-1 Protease Inhibitors2011In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 100, no 9, p. 3763-3772Article in journal (Refereed)
    Abstract [en]

    The primary aim of this study was to identify structural features that alter the intestinal epithelial permeability and efflux in a series of novel HIV-1 protease inhibitors (PIs). Eleven PIs were selected containing a tertiary alcohol in a transition-state mimicking scaffold, in which two substituents (R1 and R2) were varied systematically. Indinavir was selected as a reference compound. The apical-to-basolateral permeability was investigated in 2/4/A1 and Caco-2 monolayers. In addition, the basolateral-to-apical permeability was investigated in the Caco-2 monolayers and the efflux ratios were calculated. The absence of active drug transport processes in 2/4/A1 cells allowed identification and modeling of structural elements affecting the passive permeability. For instance, small aromatic R1 substituents and a small (bromo-) R2 substituent were associated with a high passive permeability. Efflux studies in Caco-2 cells indicated that amide-substituted neutral hydrophobic amino acids, such as valine and leucine, in the R1 position, reduced the apical-to-basolateral transport and enhanced the efflux. We conclude that our investigation revealed structural features that alter the intestinal epithelial permeability and efflux in the series of PIs and hope that these results can contribute to the synthesis of PIs with improved permeability and limited efflux properties.

  • 40.
    Mahlin, Denny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Early drug development predictions of glass-forming ability and physical stability of drugs2013In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 49, no 2, p. 323-332Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate if rapidly measured physical properties can predict glass-forming ability and glass stability of drug compounds. A series of 50 structurally diverse drug molecules were studied with respect to glass-forming ability and, for glass-formers (n = 24), the physical stability upon 1 month of storage was determined. Spray-drying and melt-cooling were used to produce the amorphous material and the solid state was analysed by Differential Scanning Calorimetry (DSC) and Powder X-ray Diffraction. Thermal properties and molecular weight (Mw) were used to develop predictive models of (i) glass-forming ability and (ii) physical stability. In total, the glass-forming ability was correctly predicted for 90% of the drugs from their Mw alone. As a rule of thumb, drugs with Mw greater than 300 g/mole are expected to be transformed to its amorphous state by using standard process technology. Glass transition temperature and Mw predicted the physical stability upon storage correctly for 78% of the glass-forming compounds. A strong sigmoidal relationship (R-2 of 0.96) was identified between crystallization temperature and stability. These findings have the potential to rationalize decisions schemes for utilizing and developing amorphous formulations, through early predictions of glass-forming ability from Mw and physical stability from simple DSC characterization.

  • 41.
    Mahlin, Denny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ponnambalam, Sopana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hockerfelt, Mina Heidarian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Toward In Silico Prediction of Glass-Forming Ability from Molecular Structure Alone: A Screening Tool in Early Drug Development2011In: Molecular Pharmaceutics, ISSN 1543-8384, Vol. 8, no 2, p. 498-506Article in journal (Refereed)
    Abstract [en]

    We present a novel computational tool which predicts the glass-forming ability of drug compounds solely from their molecular structure. Compounds which show solid-state limited aqueous solubility were selected, and their glass-forming ability was determined upon spray-drying, melt-quenching and mechanical activation. The solids produced were analyzed by differential scanning calorimetry (DSC) and powder X-ray diffraction. Compounds becoming at least partially amorphous on processing were classified as glass-formers, whereas those remaining crystalline regardless of the process method were classified as non-glass-forming compounds. A predictive model of the glass-forming ability, designed to separate between these two classes, was developed through the use of partial least-squares projection to latent structure discriminant analysis (PLS-DA) and calculated molecular descriptors. In total, ten of the 16 compounds were determined experimentally to be good glass-formers and the PLS-DA model correctly sorted 15 of the compounds using four molecular descriptors only. An external test set was predicted with an accuracy of 75%, and, hence, the PLS-DA model developed was shown to be applicable for the identification of compounds that have the potential to be designed as amorphous formulations. The model suggests that larger molecules with a low number of benzene rings, low level of molecular symmetry, branched carbon skeletons and electronegative atoms have the ability to form a glass. To conclude, we have developed a predictive, transparent and interpretable computational model for the identification of drug molecules capable of being glass-formers. The model allows an assessment of amorphization as a formulation strategy in the early drug development process, and can be applied before compound synthesis.

  • 42.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Computational modeling to predict the functions and impact of drug transporters2015In: In silico pharmacology, ISSN 2193-9616, Vol. 3, no 1, article id 8Article in journal (Refereed)
    Abstract [en]

    Transport proteins are important mediators of cellular drug influx and efflux and play crucial roles in drug distribution, disposition and clearance. Drug-drug interactions have increasingly been found to occur at the transporter level and, hence, computational tools for studying drug-transporter interactions have gained in interest. In this short review, we present the most important transport proteins for drug influx and efflux. Computational tools for predicting and understanding the substrate and inhibitor interactions with these membrane-bound proteins are discussed. We have primarily focused on ligand-based and structure-based modeling, for which the state-of-the-art and future challenges are also discussed.

  • 43.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Englund, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Ahlin, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)2007In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 323, no 1, p. 19-30Article in journal (Refereed)
    Abstract [en]

    In this article, we explore the entire structural space of registered drugs to obtain a global model for the inhibition of the drug efflux transporter breast cancer resistance protein (BCRP; ABCG2). For this purpose, the inhibitory effect of 123 structurally diverse drugs and drug-like compounds on mitoxantrone efflux was studied in Saos-2 cells transfected with human wild-type (Arg482) BCRP. The search for BCRP inhibitors throughout the drug-like chemical space resulted in the identification of 29 previously unknown inhibitors. The frequency of BCRP inhibition was 3 times higher for compounds reported to interact with other ATP-binding cassette (ABC) transporters than for compounds without reported ABC transporter affinity. An easily interpreted computational model capable of discriminating inhibitors from noninhibitors using only two molecular descriptors, octanol-water partition coefficient at pH 7.4 and molecular polarizability, was constructed. The discriminating power of this two-descriptor model was 93% for the training set and 79% for the test set, respectively. The results were supported by a global pharmacophore model and are in agreement with a two-step mechanism for the inhibition of BCRP, where both the drug's capacity to insert into the cell membrane and to interact with the inhibitory binding site of the transporter are important.

  • 44. Norinder, U
    et al.
    Bergström, C
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Prediction of ADMET Properties.2006In: ChemMedChem, ISSN 1860-7179, Vol. 1, no 9, p. 920-937Article in journal (Refereed)
  • 45.
    Norinder, Ulf
    et al.
    AstraZeneca R&D Södertälje.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Prediction of ADMET Properties2006In: ChemMedChem, Vol. 1, no 9, p. 920-937Article, review/survey (Refereed)
    Abstract [en]

    This Review describes some of the approaches and techniques used today to derive in silico models for the prediction of ADMET properties. The article also discusses some of the fundamental requirements for deriving statistically sound and predictive ADMET relationships as well as some of the pitfalls and problems encountered during these investigations. It is the intension of the authors to make the reader aware of some of the challenges involved in deriving useful in silico ADMET models for drug development.

  • 46.
    Norinder, Ulf
    et al.
    AstraZeneca R&D Södertälje.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Prediction of ADMET Properties2007In: Chemical Biology: From Small Molecules to Systems Biology and Drug Design / [ed] Schreiber, Stuart L.; Kapoor, Tarun M.; Wess, Günther, Wernheim: Wiley-VCH , 2007, p. 1003-1044Chapter in book (Other academic)
  • 47.
    Pedersen, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Slepenkin, Anatoly
    Andersson, Sara B. E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fagerberg, Jonas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Peterson, Ellena M.
    Formulation of the Microbicide INP0341 for In Vivo Protection against a Vaginal Challenge by Chlamydia trachomatis2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 10, p. e110918-Article in journal (Refereed)
    Abstract [en]

    The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.

  • 48.
    Pedersen, Jenny M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. QPS LLC, Durham, NC USA..
    Khan, Elin K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Palm, Johan
    AstraZeneca R&D Gothenburg, Pharmaceut Technol & Dev, SE-43183 Molndal, Sweden..
    Hoogstraate, Janet
    AstraZeneca R&D, CNS, Sodertalje, Sweden.;AstraZeneca R&D, Pain Innovat Med DMPK, Sodertalje, Sweden.;Valneva Sweden AB, Solna, Sweden..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Substrate and method dependent inhibition of three ABC-transporters (MDR1, BCRP, and MRP2)2017In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 103, p. 70-76Article in journal (Refereed)
    Abstract [en]

    Drug transport and drug-drug interactions (DDI) with human ABC transporters are generally investigated in mammalian cell lines or inverted membrane vesicles from insect cells (Sf9) overexpressing the transporter of interest. In this study, we instead used membrane vesicles from human embryonic kidney cells (HEK293) overexpressing wild type MDR1/Pgp (ABCB1), BCRP (ABCG2), and MRP2 (ABCC2) with the aim to study the concentration dependent inhibition of shared and prototypic probe substrates. We first investigated 15 substrates and identified estrone-17-beta-glucorinide (E17G) as shared substrate. Nine specific and general inhibitors were then studied using El7G and prototypic probe substrates. The results were compared with those previously obtained in Sf9 vesicles and cell lines of canine (MDCKII) and human (Saos-2) origin. For the majority of inhibitors, K-i; values differed <10-fold between EI7G and probe substrates. Significant differences in K-i; values were observed for about one third of the inhibitors. The transport inhibition potencies in HEK293 vesicles were in good agreement with those obtained in Sf9 vesicles. Large differences were found in the inhibition potencies observed in the vesicular systems compared to the cellular systems. Nevertheless, the rank order correlations between the different experimental systems were generally good. Our study provides further information on substrate dependent inhibition of ABC-transporters, and suggests that simple ranking of compounds can be used as a tier one approach to bridge results obtained in different experimental systems.

  • 49.
    Pedersen, Jenny M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hoogstraate, Janet
    Acturum Life Science AB, Södertälje, Sweden.
    Norén, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    LeCluyse, Edward L.
    The Hamner Institutes for Health Sciences, North Carolina, USA.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Early Identification of Clinically Relevant Drug Interactions with the Human Bile Salt Export Pump (BSEP; ABCB11)2013In: Toxicological Sciences, ISSN 1096-6080, E-ISSN 1096-0929, Vol. 136, no 2, p. 328-343Article in journal (Other academic)
    Abstract [en]

    A comprehensive analysis was performed to investigate how inhibition of the human bile salt export pump (BSEP/ABCB11) relates to clinically observed drug induced liver injury (DILI). Inhibition of taurocholate (TA) transport was investigated in BSEP membrane vesicles for a dataset of 250 compounds, and 86 BSEP inhibitors were identified. Structure-activity modeling identified BSEP inhibition to correlate strongly with compound lipophilicity, while positive molecular charge was associated with a lack of inhibition. All approved drugs in the dataset (n=182) were categorized according to DILI warnings in drug labels issued by the FDA and a strong correlation between BSEP inhibition and DILI was identified. As many as 38 of the 61 identified BSEP inhibitors were associated with severe DILI, including nine drugs not previously linked to BSEP inhibition. Further, among the tested compounds, every second drug associated with severe DILI was a BSEP inhibitor. Finally, sandwich cultured human hepatocytes (SCHH) were used to investigate the relationship between BSEP inhibition, TA transport and clinically observed DILI in detail. BSEP inhibitors associated with severe DILI greatly reduced the TA canalicular efflux while BSEP inhibitors with less severe or no DILI resulted in weak or no reduction of TA efflux in SCHH. This distinction illustrates the usefulness of SCHH in refined analysis of BSEP inhibition. In conclusion, BSEP inhibition in membrane vesicles was found to correlate to DILI severity, and altered disposition of TA in SCHH  was shown to separate BSEP inhibitors associated with severe DILI from those with no or mild DILI. 

  • 50.
    Pedersen, Jenny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A. S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hoogstraate, Janet
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2)2008In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 11, p. 3275-3287Article in journal (Refereed)
    Abstract [en]

    The chemical space of registered oral drugs was explored for inhibitors of the human multidrug-resistance associated protein 2 (MRP2, ABCC2), using a data set of 191 structurally diverse drugs and drug-like compounds. The data set included a new reference set of 75 compounds, for studies of hepatic drug interactions with transport proteins, CYP enzymes, and compounds associated with liver toxicity. The inhibition of MRP2-mediated transport of estradiol-17 beta-D-glucuronide was studied in inverted membrane vesicles from Sf9 cells overexpressing human MRP2. A total of 27 previously unknown MRP2 inhibitors were identified, and the results indicate an overlapping but narrower inhibitor space for MRP2 compared with the two other major ABC efflux transporters P-gp (ABCB1) and BCRP (ABCG2). In addition, 13 compounds were shown to stimulate the transport of cstradiol-17 beta-D-glucuronide. The experimental results were used to develop a computational model able to discriminate inhibitors from noninhibitors according to their molecular structure, resulting in a predictive power of 86% for the training set and 72% for the test set. The inhibitors were in general larger and more lipophilic and presented a higher aromaticity than the noninhibitors. The developed computational model is applicable in an early stage of the drug discovery process and is proposed as a tool for prediction of MRP2-mediated hepatic drug interactions and toxicity.

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