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Membrane transporters in drug development and as determinants of precision medicine

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From Nature Reviews Drug Discovery

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Abstract

The effect of membrane transporters on drug disposition, efficacy and safety is now well recognized. Since the initial publication from the International Transporter Consortium, significant progress has been made in understanding the roles and functions of transporters, as well as in the development of tools and models to assess and predict transporter-mediated activity, toxicity and drug–drug interactions (DDIs). Notable advances include an increased understanding of the effects of intrinsic and extrinsic factors on transporter activity, the application of physiologically based pharmacokinetic modelling in predicting transporter-mediated drug disposition, the identification of endogenous biomarkers to assess transporter-mediated DDIs and the determination of the cryogenic electron microscopy structures of SLC and ABC transporters. This article provides an overview of these key developments, highlighting unanswered questions, regulatory considerations and future directions.

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Fig. 1: Clinically important uptake and efflux transporters in plasma membranes.
Fig. 2: Intrinsic (pink) and extrinsic (blue) factors affecting the abundance and/or activity of drug transport proteins and mechanisms that may be involved, including specific regulatory pathways and/or inhibitory effects.
Fig. 3: Development, validation and applications of physiologically based pharmacokinetic models of transporter-mediated processes.
Fig. 4: Classification of endogenous biomarkers of hepatic and renal transporters and International Transporter Consortium recommendations for their application in drug development.
Fig. 5: Decision tree for organic anion transporting polypeptide (OATP1B)-mediated drug–drug interaction risk assessment with coproporphyrin I.
Fig. 6: Drug-induced organ injury.

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Acknowledgements

The authors thank members of the International Transporter Consortium (ITC) for review of the article before submission, in particular V. Arya, C. Lee, M. Piquette-Miller and M. Taub.

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Author notes

  1. These authors contributed equally: Aleksandra Galetin, Kim L. R. Brouwer.

Authors and Affiliations

  1. Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, UK

    Aleksandra Galetin

  2. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Kim L. R. Brouwer

  3. Independent Consultant, Guilford, CT, USA

    Donald Tweedie

  4. Clinical Pharmacology, Genentech Research and Early Development, South San Francisco, CA, USA

    Kenta Yoshida

  5. Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

    Noora Sjöstedt

  6. Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA

    Lauren Aleksunes

  7. Department of Pharmacokinetics, Dynamics, Metabolism, and Bioanalytics, Merck & Co., Inc., Rahway, NJ, USA

    Xiaoyan Chu & Michael J. Hafey

  8. Preclinical Sciences and Translational Safety, Johnson & Johnson, Janssen Pharmaceuticals, Spring House, PA, USA

    Raymond Evers

  9. Drug Metabolism, Gilead Sciences Inc., Foster City, CA, USA

    Yurong Lai

  10. Department of Pharmacology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Pär Matsson

  11. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA

    Andrew Riselli, Jia Yang, Sook Wah Yee & Kathleen M. Giacomini

  12. Department of Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb Research and Development, Princeton, NJ, USA

    Hong Shen

  13. Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Alex Sparreboom

  14. Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Worldwide R&D, Pfizer Inc, Groton, CT, USA

    Manthena V. S. Varma

  15. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA

    Xinning Yang

  16. Drug Metabolism and PK, GlaxoSmithKline, Collegeville, PA, USA

    Maciej J. Zamek-Gliszczynski

  17. Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA

    Lei Zhang

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  1. Aleksandra Galetin
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Competing interests

A.G. is a deputy director of the Centre for Applied Pharmacokinetic Research, which is a consortium of companies including Genentech, Roche, Merck Serono, Takeda, Janssen, GSK, Servier, Amgen, Eli Lilly and Abbvie. She receives funding from A*STAR (BM/NDR/19/003), Research Council of Norway (15451500) and Asahi Kasei Pharma Corporation for her PhD students and trainees, and she is an unpaid President of the International Society for the Study of Xenobiotics. D.T. owns stock and/or stock options in Merck & Co., Inc. and receives free membership in the International Society for the Study of Xenobiotics. H.S. is an employee of Bristol Myers Squibb and owns stock and/or stock options in Bristol Myers Squibb. K.L.R.B. is co-inventor of the sandwich-cultured hepatocyte technology for quantification of biliary excretion (B-CLEAR) and related technologies, which have been licensed exclusively to Qualyst Transporter Solutions, acquired by BioIVT. She receives funding from a Certara Simcyp Grant and Partnership Scheme to support a PhD student in her laboratory and serves as an unpaid member of the scientific advisory committee for the International Society for the Study of Xenobiotics. K.Y. is an employee of Genentech and owns stock and/or stock options in Genentech and Roche. L.A. serves in an unpaid position for the Society of Toxicology. M.J.H. and X.C. are employees of Merck & Co., Inc. and own stock and/or stock options in Merck & Co., Inc. M.J.Z.-G. is an employee of GlaxoSmithKline and owns stock and/or stock options in GlaxoSmithKline. He also serves in an unpaid position for the American Society for Clinical Pharmacology and Therapeutics. M.V.S.V is an employee of Pfizer and owns stock and/or stock options in Pfizer. N.S. receives funding for graduate student support from the Sigrid Jusélius Foundation. R.E. is an employee of Johnson & Johnson and owns stock and/or stock options in Johnson & Johnson. Y.L. is an employee of Gilead Sciences, Inc. and owns stock and/or stock options in Gilead Sciences, Inc. K.M.G. and S.W.Y. are co-founders of Apricity Therapeutics, Inc., a transporter-based biotechnology company. A.R., J.Y., L.Z., P.M. and X.Y. declare no competing interests.

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Funding

A.R. is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) under award number 5T32GM007546. A.S. is supported, in part, by the NIH under award numbers R01CA238946, R01GM139936 and U24CA247648 and by the Ohio State University Comprehensive Cancer Center Pelotonia Foundation. K.L.R.B. is supported, in part, by the National Institute of General Medical Sciences of the NIH under award number R35GM122576. K.M.G. and S.W.Y. are supported, in part, by the NIH under award numbers R01GM139875, R01GM117163 and UC2HD113474. K.M.G. is also supported, in part by the grant number U01FD004979/U01FD005978 from the FDA, which supports the University of California–San Francisco (UCSF)-Stanford Center of Excellence in Regulatory Sciences and Innovation. L.A is supported, in part, by the NIH under award numbers UC2HD113039, P30ES005022, R01GM123330 and R01ES029275. N.S. is supported, in part, by the Sigrid Jusélius Foundation.

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Galetin, A., Brouwer, K.L.R., Tweedie, D. et al. Membrane transporters in drug development and as determinants of precision medicine. Nat Rev Drug Discov 23, 255–280 (2024). https://doi.org/10.1038/s41573-023-00877-1

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