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  • 1.
    Artursson, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Cell culture absorption models - state of the art2006In: Pharmacokinetic profiling in drug research: Biological. physicochemical and computational stragies, Wiley-VCH, Zürich , 2006, p. 71-Chapter in book (Refereed)
  • 2.
    Artursson, P
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Neuhoff, S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Tavelin, S
    Matsson, P
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Passive permeability and active transport models for the prediction of oral absorption2007In: Comprehensive medicinal chemistry vol 5: Cellular in vitro tools in ADMET, Elsevier , 2007, p. 259-278Chapter in book (Refereed)
  • 3.
    Artursson, Per
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Pär
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Absorption Prediction2004In: Profiling in Drug Discovery for Lead Selection, AAPS Press, Arlington VA , 2004Chapter in book (Refereed)
  • 4.
    Artursson, Per
    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.
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    In vitro characterization of interactions with drug transporting proteins2013In: Transporters in Drug Development : Discovery, Optimization, Clinical Study and Regulation / [ed] Steffansen B, Sugiyama Y, New York: Springer, 2013, p. 37-65Chapter in book (Refereed)
  • 5. Chu, X.
    et al.
    Korzekwa, K.
    Elsby, R.
    Fenner, K.
    Galetin, A.
    Lai, Y.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Moss, A.
    Nagar, S.
    Rosania, G. R.
    Bai, J. P. F.
    Polli, J. W.
    Sugiyama, Y.
    Brouwer, K. L. R.
    Intracellular Drug Concentrations and Transporters: Measurement, Modeling, and Implications for the Liver2013In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 94, no 1, p. 126-141Article, review/survey (Refereed)
    Abstract [en]

    Intracellular concentrations of drugs and metabolites are often important determinants of efficacy, toxicity, and drug interactions. Hepatic drug distribution can be affected by many factors, including physicochemical properties, uptake/efflux transporters, protein binding, organelle sequestration, and metabolism.This white paper highlights determinants of hepatocyte drug/metabolite concentrations and provides an update on model systems, methods, and modeling/simulation approaches used to quantitatively assess hepatocellular concentrations of molecules. The critical scientific gaps and future research directions in this field are discussed.

  • 6.
    Guo, Yingying
    et al.
    Eli Lilly & Co, Lilly Corp Ctr, Invest Drug Disposit, Indianapolis, IN 46285 USA.
    Chu, Xiaoyan
    Merck & Co Inc, Depat Pharmacokinet Pharmacodynam & Drug Metab, Kenilworth, NJ USA.
    Parrott, Neil J.
    F Hoffmann La Roche Ltd, Roche Innovat Ctr Basel, Pharmaceut Sci Pharmaceut Res & Early Dev, Basel, Switzerland.
    Brouwer, Kim L. R.
    Univ N Carolina, UNC Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27515 USA.
    Hsu, Vicky
    US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Nagar, Swati
    Temple Univ, Sch Pharm, Dept Pharmaceut Sci, Philadelphia, PA 19122 USA.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Sharma, Pradeep
    AstraZeneca R&D, IMED Biotech Unit, Safety & ADME Translat Sci Drug Safety & Metab, Cambridge, England.
    Snoeys, Jan
    Janssen R&D, Dept Pharmacokinet Dynam & Metab, Beerse, Belgium.
    Sugiyama, Yuichi
    RIKEN, Res Cluster Innovat, RIKEN Innovat Ctr, Sugiyama Lab, Yokohama, Kanagawa, Japan.
    Tatosian, Daniel
    Merck & Co Inc, Depat Pharmacokinet Pharmacodynam & Drug Metab, Kenilworth, NJ USA.
    Unadkat, Jashvant D.
    Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA.
    Huang, Shiew-Mei
    US FDA, Off Clin Pharmacol, Off Translat Sci, Ctr Drug Evaluat & Res, Silver Spring, MD USA.
    Galetin, Aleksandra
    Univ Manchester, Sch Hlth Sci, Ctr Appl Pharmacokinet Res, Manchester, Lancs, England.
    Advancing Predictions of Tissue and Intracellular Drug Concentrations Using In Vitro, Imaging and Physiologically Based Pharmacokinetic Modeling Approaches2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 5, p. 865-889Article, review/survey (Refereed)
    Abstract [en]

    This white paper examines recent progress, applications, and challenges in predicting unbound and total tissue and intra/subcellular drug concentrations using in vitro and preclinical models, imaging techniques, and physiologically based pharmacokinetic (PBPK) modeling. Published examples, regulatory submissions, and case studies illustrate the application of different types of data in drug development to support modeling and decision making for compounds with transporter-mediated disposition, and likely disconnects between tissue and systemic drug exposure. The goals of this article are to illustrate current best practices and outline practical strategies for selecting appropriate in vitro and in vivo experimental methods to estimate or predict tissue and plasma concentrations, and to use these data in the application of PBPK modeling for human pharmacokinetic (PK), efficacy, and safety assessment in drug development.

  • 7.
    Mateus, André
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Gordon, Laurie J.
    GlaxoSmithKline, Platform Technol & Sci, Stevenage SG1 2NY, Herts, England..
    Wayne, Gareth J.
    GlaxoSmithKline, Dept Target & Pathway Validat, Stevenage SG1 2NY, Herts, England..
    Almqvist, Helena
    Karolinska Inst, Div Translat Med, Labs Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17165 Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Chem Biol, Solna, Sweden..
    Axelsson, Hanna
    Karolinska Inst, Div Translat Med, Labs Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17165 Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Chem Biol, Solna, Sweden..
    Seashore-Ludlow, Brinton
    Karolinska Inst, Div Translat Med, Labs Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17165 Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Chem Biol, Solna, Sweden..
    Treyer, Andrea
    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.
    Lundbäck, Thomas
    Karolinska Inst, Div Translat Med, Labs Chem Biol, Chem Biol Consortium Sweden,Sci Life Lab, SE-17165 Solna, Sweden.;Karolinska Inst, Dept Med Biochem & Biophys, Chem Biol, Solna, Sweden..
    West, Andy
    GlaxoSmithKline, Platform Technol & Sci, Stevenage SG1 2NY, Herts, England..
    Hann, Michael M.
    GlaxoSmithKline, Platform Technol & Sci, Stevenage SG1 2NY, Herts, England..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery2017In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 114, no 30, p. E6231-E6239Article in journal (Refereed)
    Abstract [en]

    Inadequate target exposure is a major cause of high attrition in drug discovery. Here, we show that a label-free method for quantifying the intracellular bioavailability (F-ic) of drug molecules predicts drug access to intracellular targets and hence, pharmacological effect. We determined F-ic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation, and dementia. Both cytosolic targets and targets localized in subcellular compartments were investigated. F-ic gives insights on membrane-permeable compounds in terms of cellular potency and intracellular target engagement, compared with biochemical potency measurements alone. Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful tool for compound selection in early drug discovery.

  • 8.
    Mateus, André
    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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    A High-Throughput Cell-Based Method to Predict the Unbound Drug Fraction in the Brain2014In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 7, p. 3005-3010Article in journal (Refereed)
    Abstract [en]

    Optimization of drug efficacy in the brain requires understanding of the local exposure to unbound drug at the site of action. This relies on measurements of the unbound drug fraction (f(u,brain)), which currently requires access to brain tissue. Here, we present a novel methodology using homogenates of cultured cells for rapid estimation of f(u,brain). In our setup, drug binding to human embryonic kidney cell (HEK293) homogenate was measured in a small-scale dialysis apparatus. To increase throughput, we combined drugs into cassettes for simultaneous measurement of multiple compounds. Our method estimated f(u,brain) with an average error of 1.9-fold. We propose that our simple method can be used as an inexpensive, easily available and high-throughput alternative to brain tissues excised from laboratory animals. Thereby, estimates of unbound drug exposure can now implemented at a much earlier stage of the drug discovery process, when molecular property changes are easier to make.

  • 9.
    Mateus, André
    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.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Rapid Measurement of Intracellular Unbound Drug Concentrations2013In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 10, no 6, p. 2467-2478Article in journal (Refereed)
    Abstract [en]

    Intracellular unbound drug concentrations determine affinity to targets in the cell interior. However, due to difficulties in measuring them, they are often overlooked in pharmacology. Here we present a simple experimental technique for the determination of unbound intracellular drug concentrations in cultured cells that is based on parallel measurements of cellular drug binding and steady-state intracellular drug concentrations. Binding in HEK293 cells was highly correlated with binding in liver-derived systems, whereas binding in plasma did not compare well with cellular binding. Compound lipophilicity increased drug binding, while negative charge and aromatic functional groups decreased binding. Intracellular accumulation of unbound drug was consistent with pH dependent subcellular sequestration, as confirmed by modeling and by inhibition of subcellular pH gradients. The approach developed here can be used to measure intracellular unbound drug concentrations in more complex systems, for example, cell lines with controlled expression of transporters and enzymes or primary cells.

  • 10.
    Mateus, André
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Treyer, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Matsson, Par
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Karlgren, Maria
    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.
    Impact of drug transporters on intracellular unbound drug concentrations2016In: Drug metabolism reviews (Softcover ed.), ISSN 0360-2532, E-ISSN 1097-9883, Vol. 48, p. 147-147Article in journal (Other academic)
  • 11.
    Mateus, André
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Treyer, Andrea
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wegler, Christine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. AstraZeneca R&D, Cardiovasc & Metab Dis Innovat Med, DMPK, SE-43183 Molndal, Sweden..
    Karlgren, Maria
    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.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Intracellular drug bioavailability: a new predictor of system dependent drug disposition2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, p. 1-12, article id 43047Article in journal (Refereed)
    Abstract [en]

    Intracellular drug exposure is influenced by cell-and tissue-dependent expression of drug-transporting proteins and metabolizing enzymes. Here, we introduce the concept of intracellular bioavailability (F-ic) as the fraction of extracellular drug available to bind intracellular targets, and we assess how Fic is affected by cellular drug disposition processes. We first investigated the impact of two essential drug transporters separately, one influx transporter (OATP1B1; SLCO1B1) and one efflux transporter (P-gp; ABCB1), in cells overexpressing these proteins. We showed that OATP1B1 increased Fic of its substrates, while P-gp decreased Fic. We then investigated the impact of the concerted action of multiple transporters and metabolizing enzymes in freshly-isolated human hepatocytes in culture configurations with different levels of expression and activity of these proteins. We observed that Fic was up to 35-fold lower in the configuration with high expression of drug-eliminating transporters and enzymes. We conclude that Fic provides a measurement of the net impact of all cellular drug disposition processes on intracellular bioavailable drug levels. Importantly, no prior knowledge of the involved drug distribution pathways is required, allowing for high-throughput determination of drug access to intracellular targets in highly defined cell systems (e.g., single-transporter transfectants) or in complex ones (including primary human cells).

  • 12.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Computational Prospecting for Drug-Transporter Interactions2013In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 94, no 1, p. 30-32Article in journal (Refereed)
    Abstract [en]

    Membrane transporters are recognized as important determinants of drug disposition, action, and adverse events, yet our understanding of the molecular determinants of drug-transporter interactions is limited. Here, we discuss how computational analysis of transporter amino acid sequence, transporter structure, and ligand chemistry can be used to explore transporter function at the molecular level and to predict interactions with drug molecules.

  • 13.
    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.

  • 14.
    Matsson, Pär
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Bergström, Christel A S
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Nagahara, Naoki
    Tavelin, Staffan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Norinder, Ulf
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Artursson, Per
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
    Exploring the role of different drug transport routes in permeability screening.2005In: J Med Chem, ISSN 0022-2623, Vol. 48, no 2, p. 604-13Article in journal (Refereed)
  • 15.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Doak, Bradley C.
    Monash Univ, Dept Med Chem, MIPS, 381 Royal Parade, Parkville, Vic, Australia..
    Over, Björn
    AstraZeneca, Cardiovasc & Metab Dis, Innovat Med & Early Dev Biotech Unit, Pepparedsleden 1, SE-43183 Molndal, Sweden..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Cell permeability beyond the rule of 52016In: Advanced Drug Delivery Reviews, ISSN 0169-409X, E-ISSN 1872-8294, Vol. 101, p. 42-61Article, review/survey (Refereed)
    Abstract [en]

    Drug discovery for difficult targets that have large and flat binding sites is often better suited to compounds beyond the "rule of 5" (bRo5). However, such compounds carry higher pharmacokinetic risks, such as low solubility and permeability, and increased efflux and metabolism. Interestingly, recent drug approvals and studies suggest that cell permeable and orally bioavailable drugs can be discovered far into bRo5 space. Tactics such as reduction or shielding of polarity by N-methylation, bulky side chains and intramolecular hydrogen bonds may be used to increase cell permeability in this space, but often results in decreased solubility. Conformationally flexible compounds can, however, combine high permeability and solubility, properties that are keys for cell permeability and intestinal absorption. Recent developments in computational conformational analysis will aid design of such compounds and hence prediction of cell permeability. Transporter mediated efflux occurs for most investigated drugs in bRo5 space, however it is commonly overcome by high local intestinal concentrations on oral administration. In contrast, there is little data to support significant impact of transporter-mediated intestinal absorption in bRo5 space. Current knowledge of compound properties that govern transporter effects of bRo5 drugs is limited and requires further fundamental and comprehensive studies.

  • 16.
    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.

  • 17.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fenu, Luca A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundquist, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wisniewski, Jacek R.
    Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, D-82152 Martinsried, Germany..
    Kansy, Manfred
    F Hoffmann La Roche & Co Ltd, Roche Innovat Ctr Basel, Pharmaceut Sci, Roche Pharmaceut Res & Early Dev, CH-4070 Basel, Switzerland..
    Artursson, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Addendum to 'Quantifying the impact of transporters on cellular drug permeability'2015In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 36, no 9, p. 559-559Article in journal (Refereed)
  • 18.
    Matsson, Pär
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Fenu, Luca A
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundquist, Patrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wiśniewski, Jacek R
    Kansy, Manfred
    Artursson, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Quantifying the impact of transporters on cellular drug permeability.2015In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 35, no 5, p. 255-262Article in journal (Refereed)
    Abstract [en]

    The conventional model of drug permeability has recently been challenged. An alternative model proposes that transporter-mediated flux is the sole mechanism of cellular drug permeation, instead of existing in parallel with passive transmembrane diffusion. We examined a central assumption of this alternative hypothesis; namely, that transporters can give rise to experimental observations that would typically be explained with passive transmembrane diffusion. Using systems-biology simulations based on available transporter kinetics and proteomic expression data, we found that such observations are possible in the absence of transmembrane diffusion, but only under very specific conditions that rarely or never occur for known human drug transporters.

  • 19.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Giacomini, Kathleen M.
    University of California San Francisco.
    Brater, David Craig
    Renal Disposition of Drugs and Translation to Dosing Strategies2013In: Seldin and Giebisch's The Kidney   : Physiology and Pathophysiology / [ed] Alpern R, Caplan M, Moe O, Oxford: Academic Press, 2013, 5, p. 3185-3214Chapter in book (Refereed)
  • 20.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    How Big Is Too Big for Cell Permeability?2017In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 5, p. 1662-1664Article in journal (Refereed)
    Abstract [en]

    Understanding how to design cell permeable ligands for intracellular targets that have difficult binding sites, such as protein protein interactions, would open vast opportunities for drug discovery. Interestingly, libraries of cyclic peptides displayed a steep drop-off in membrane permeability at molecular weights above 1000 Da and it appears likely that this cutoff constitutes an upper size limit also for more druglike compounds. However, chemical space from 500 to 1000 Da remains virtually unexplored and represents a vast opportunity for those prepared to venture into new territories of drug discovery.

  • 21.
    Matsson, Pär X.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundquist, Patrik
    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.
    The Need for Speed-Kinetic Limits of Drug Transporters2016In: TIPS - Trends in Pharmacological Sciences, ISSN 0165-6147, E-ISSN 1873-3735, Vol. 37, no 4, p. 243-245Article in journal (Refereed)
  • 22.
    Matsson, Pär
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Yee, S W
    Markova, S
    Morrissey, K
    Jenkins, G
    Xuan, J
    Jorgenson, E
    Kroetz, D L
    Giacomini, K M
    Discovery of regulatory elements in human ATP-binding cassette transporters through expression quantitative trait mapping2012In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 12, p. 214-226Article in journal (Refereed)
    Abstract [en]

    ATP-binding cassette (ABC) membrane transporters determine the disposition of many drugs, metabolites and endogenous compounds. Coding region variation in ABC transporters is the cause of many genetic disorders, but much less is known about the genetic basis and functional outcome of ABC transporter expression level variation. We used genotype and mRNA transcript level data from human lymphoblastoid cell lines to assess population and gender differences in ABC transporter expression, and to guide the discovery of genomic regions involved in transcriptional regulation. Nineteen of 49 ABC genes were differentially expressed between individuals of African, Asian and European descent, suggesting an important influence of race on expression level of ABC transporters. Twenty-four significant associations were found between transporter transcript levels and proximally located genetic variants. Several of the associations were experimentally validated in reporter assays. Through influencing ABC expression levels, these single-nucleotide polymorphisms may affect disease susceptibility and response to drugs.

  • 23.
    Over, Bjorn
    et al.
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Molndal, Sweden..
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tyrchan, Christian
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Doak, Bradley C.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Foley, Michael A.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Triinst Therapeut Discovery Inst, New York, NY USA..
    Hilgendorf, Constanze
    AstraZeneca R&D Gothenburg, Safety & ADME Translat Sci, Drug Safety & Metab, Molndal, Sweden..
    Johnston, Stephen E.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA..
    Lee, Maurice D.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Lewis, Richard J.
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Resp Inflammat & Autoimmun Dis, Molndal, Sweden..
    McCarren, Patrick
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA..
    Muncipinto, Giovanni
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Norinder, Ulf
    Swedish Toxicol Sci Res Ctr, Sodertalje, Sweden..
    Perry, Matthew W. D.
    Duvall, Jeremy R.
    Broad Inst, Ctr Sci Therapeut, Cambridge, MA 02142 USA.;Ensemble Therapeut, Cambridge, MA 02139 USA..
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Structural and conformational determinants of macrocycle cell permeability2016In: Nature Chemical Biology, ISSN 1552-4450, E-ISSN 1552-4469, Vol. 12, no 12, p. 1065-+Article in journal (Refereed)
    Abstract [en]

    Macrocycles are of increasing interest as chemical probes and drugs for intractable targets like protein-protein interactions, but the determinants of their cell permeability and oral absorption are poorly understood. To enable rational design of cell-permeable macrocycles, we generated an extensive data set under consistent experimental conditions for more than 200 nonpeptidic, de novo-designed macrocycles from the Broad Institute's diversity-oriented screening collection. This revealed how specific functional groups, substituents and molecular properties impact cell permeability. Analysis of energy-minimized structures for stereo- and regioisomeric sets provided fundamental insight into how dynamic, intramolecular interactions in the 3D conformations of macrocycles may be linked to physicochemical properties and permeability. Combined use of quantitative structure-permeability modeling and the procedure for conformational analysis now, for the first time, provides chemists with a rational approach to design cell-permeable non-peptidic macrocycles with potential for oral absorption.

  • 24. Over, Bjorn
    et al.
    McCarren, Patrick
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Foley, Michael
    Giordanetto, Fabrizio
    Gronberg, Gunnar
    Hilgendorf, Constanze
    Lee, Maurice D.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Muncipinto, Giovanni
    Pellisson, Melanie
    Perry, Matthew W. D.
    Svensson, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Duvall, Jeremy R.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Physical Organic Chemistry.
    Impact of Stereospecific Intramolecular Hydrogen Bonding on Cell Permeability and Physicochemical Properties2014In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 57, no 6, p. 2746-2754Article in journal (Refereed)
    Abstract [en]

    Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pK(a), and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH -> NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's rule of 5.

  • 25.
    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. 

  • 26.
    Schlessinger, Avner
    et al.
    Icahn Sch Med Mt Sinai, Dept Pharmacol Sci, New York, NY 10029 USA.
    Welch, Matthew A.
    Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA.
    van Vlijmen, Herman
    Janssen Res & Dev, Discovery Sci, Computat Chem, Beerse, Belgium.
    Korzekwa, Ken
    Temple Univ, Dept Pharmaceut Sci, Philadelphia, PA 19122 USA.
    Swaan, Peter W.
    Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Molecular Modeling of Drug-Transporter Interactions-An International Transporter Consortium Perspective2018In: Clinical Pharmacology and Therapeutics, ISSN 0009-9236, E-ISSN 1532-6535, Vol. 104, no 5, p. 818-835Article, review/survey (Refereed)
    Abstract [en]

    Membrane transporters play diverse roles in the pharmacokinetics and pharmacodynamics of small-molecule drugs. Understanding the mechanisms of drug-transporter interactions at the molecular level is, therefore, essential for the design of drugs with optimal therapeutic effects. This white paper examines recent progress, applications, and challenges of molecular modeling of membrane transporters, including modeling techniques that are centered on the structures of transporter ligands, and those focusing on the structures of the transporters. The goals of this article are to illustrate current best practices and future opportunities in using molecular modeling techniques to understand and predict transporter-mediated effects on drug disposition and efficacy. Membrane transporters from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate the cellular uptake, efflux, and homeostasis of many essential nutrients and significantly impact the pharmacokinetics of drugs(1-4); further, they may provide targets for novel therapeutics as well as facilitate prodrug approaches.(5,6) Because of their often broad substrate selectivity they are also implicated in many undesirable and sometimes life-threatening drug-drug interactions (DDIs).(5,6)

  • 27.
    Sebastiano, Matteo Rossi
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Doak, Bradley C.
    Monash Univ, MIPS, Dept Med Chem, Victoria, Australia.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Poongavanam, Vasanthanathan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Over, Björn
    AstraZeneca R&D Gothenburg, Innovat Med & Early Dev Biotech Unit, Cardiovasc & Metab Dis, Mölndal, Sweden.
    Ermondi, Giuseppe
    Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy.
    Caron, Giulia
    Univ Turin, Dept Mol Biotechnol & Hlth Sci, Turin, Italy.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kihlberg, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Organic Chemistry.
    Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 52018In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 61, no 9, p. 4189-4202Article in journal (Refereed)
    Abstract [en]

    Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally diverse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds’ minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous solubility depended less on the specific 3D conformation. Inspection of the crystal structures highlighted flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds as particularly effective in providing “chameleonic” properties that allow compounds to display both high cell permeability and aqueous solubility. These structural features, in combination with permeability predictions based on the correlation to solvent-accessible 3D PSA, should inspire drug design in the challenging chemical space far beyond the Ro5.

  • 28.
    Simoff, Ivailo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Karlgren, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Backlund, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala, Sweden.
    Lindström, Anne-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gaugaz, Fabienne Z.
    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.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University Drug Optimization and Pharmaceutical Profiling Platform (UDOPP), Uppsala, Sweden.
    Complete Knockout of Endogenous Mdr1 (Abcb1) in MDCK Cells by CRISPR-Cas92016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 2, p. 1017-1021Article in journal (Refereed)
    Abstract [en]

    Madin-Darby canine kidney II cells transfected with one or several transport proteins are commonly used models to study drug transport. In these cells, however, endogenous transporters such as canine Mdr1/P-glycoprotein (Abcb1) complicate the interpretation of transport studies. The aim of this investigation was to establish a Madin-Darby canine kidney II cell line using CRISPR-Cas9 gene-editing technology to knock out endogenous canine Mdr1 (cMdr1) expression. CRISPR-Cas9-mediated Abcb1 homozygous disruption occurred at frequencies of around 20% and resulted in several genotypes. We selected 1 clonal cell line, cMdr1 KO Cl2, for further examination. Consistent with an on-target effect of CRISPR-Cas9 in specific regions of the endogenous canine Abcb1 gene, we obtained a cell clone with Abcb1 gene alterations and without any cMdr1 expression, as confirmed by genome sequencing and quantitative protein analysis. Functional studies of these cells, using digoxin and other prototypic MDR1 substrates, showed close to identical transport in the apical-to-basolateral and basolateral-to-apical directions, resulting in efflux ratios indistinguishable from unity.

  • 29.
    Treyer, Andrea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mateus, André
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wisniewski, Jacek R.
    Max Planck Inst Biochem, Dept Prote & Signal Transduct, Biochem Prote Grp, D-82152 Martinsried, Germany.
    Boriss, Hinnerk
    Sovicell GmbH, D-04103 Leipzig, Germany.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala Univ, Dept Pharm, S-75123 Uppsala, Sweden.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Intracellular Drug Bioavailability: Effect of Neutral Lipids and Phospholipids2018In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 15, no 6, p. 2224-2233Article in journal (Refereed)
    Abstract [en]

    Intracellular unbound drug concentrations are the pharmacologically relevant concentrations for targets inside cells. Intracellular drug concentrations are determined by multiple processes, including the extent of drug binding to intracellular structures. The aim of this study was to evaluate the effect of neutral lipid (NL) and phospholipid (PL) levels on intracellular drug disposition. The NL and/or PL content of 3T3-L1 cells were enhanced, resulting in phenotypes (in terms of morphology and proteome) reminiscent of adipocytes (high NL and PL) or mild phospholipidosis (only high PL). Intracellular bioavailability (F-ic) was then determined for 23 drugs in these cellular models and in untreated wild-type cells. A higher PL content led to higher intracellular drug binding and a lower F-ic. The induction of NL did not further increase drug binding but led to altered F-ic due to increased lysosomal pH. Further, there was a good correlation between binding to beads coated with pure PL and intracellular drug binding. In conclusion, our results suggest that PL content is a major determinant of drug binding in cells and that PL beads may constitute a simple alternative to estimating this parameter. Further, the presence of massive amounts of intracellular NLs did not influence drug binding significantly.

  • 30.
    Wegler, Christine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Krogstad, Veronica
    Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo.
    Urdzik, Jozef
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Christensen, Hege
    Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo.
    Andersson, Tommy B
    DMPK, Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bridging differences in CYP activity between donor-matched human liver microsomes and hepatocytesManuscript (preprint) (Other academic)
  • 31.
    Ölander, Magnus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wiśniewski, Jacek R.
    Max Planck Inst Biochem, Biochem Prote Grp, Dept Prote & Signal Transduct, D-82152 Martinsried, Germany.
    Matsson, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Lundquist, Patrik
    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. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Drug Optimizat & Pharmaceut Profiling Platform, S-75123 Uppsala, Sweden.
    The Proteome of Filter-Grown Caco-2 Cells With a Focus on Proteins Involved in Drug Disposition2016In: Journal of Pharmaceutical Sciences, ISSN 0022-3549, E-ISSN 1520-6017, Vol. 105, no 2, p. 817-827Article in journal (Refereed)
    Abstract [en]

    Caco-2 cells are widely used in studies of intestinal cell physiology and drug transport. Here, the global proteome of filter-grown Caco-2 cells was quantified using the total protein approach and compared with the human colon and jejunum proteomes. In total, 8096 proteins were identified. In-depth analysis of proteins defining enterocyte differentiation—including brush-border hydrolases, integrins, and adherens and tight junctions—gave near-complete coverage of the expected proteins. Three hundred twenty-seven absorption, distribution, metabolism and excretion proteins were identified, including 112 solute carriers and 20 ATP-binding cassette transporters. OATP2B1 levels were 16-fold higher in Caco-2 cells than in jejunum. To investigate the impact of this difference on in vitro-in vivo extrapolations, we studied the uptake kinetics of the OATP2B1 substrate pitavastatin in Caco-2 monolayers, and found that the contribution of OATP2B1 was 60%-70% at clinically relevant intestinal concentrations. Pitavastatin kinetics was combined with transporter concentrations to model the contribution of active transport and membrane permeation in the jejunum. The lower OATP2B1 expression in jejunum led to a considerably lower transporter contribution (<5%), suggesting that transmembrane diffusion dominates pitavastatin absorption in vivo. In conclusion, we present the first in-depth quantification of the filter-grown Caco-2 proteome. We also demonstrate the crucial importance of considering transporter expression levels for correct interpretation of drug transport routes across the human intestine.

1 - 31 of 31
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