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Review ArticleReview Article

Transporters and Drug-Drug Interactions: Important Determinants of Drug Disposition and Effects

Jörg König, Fabian Müller and Martin F. Fromm
Martin C. Michel, ASSOCIATE EDITOR
Pharmacological Reviews July 2013, 65 (3) 944-966; DOI: https://doi.org/10.1124/pr.113.007518
Jörg König
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
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Fabian Müller
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
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Martin F. Fromm
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
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Martin C. Michel
Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany
Roles: ASSOCIATE EDITOR
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Abstract

Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs. They are localized in organs such as small intestine, liver, and kidney, which are critical for drug absorption and elimination. Moreover, they can be found in important blood-tissue barriers such as the blood-brain barrier. Inhibition or induction of drug transporters by coadministered drugs can alter pharmacokinetics and pharmacodynamics of the victim drugs. This review will summarize in particular clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters [P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)], to inhibition of hepatic uptake transporters [organic anion transporting polypeptides (OATPs)], or to inhibition of transporter-mediated [organic anion transporters (OATs), organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), P-gp] renal secretion of xenobiotics. Available data on the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug-drug interactions will be discussed. We will also present and discuss data on the variable extent to which information on the impact of transporters on drug disposition is included in summaries of product characteristics of selected countries (SPCs). Further work is required regarding a better understanding of the role of the drug metabolism–drug transport interplay for drug-drug interactions and on the extrapolation of in vitro findings to the in vivo (human) situation.

Footnotes

  • This work was supported by the German Federal Ministry of Education and Research (BMBF; Project Grant 01EX1015G); the German Cancer Aid (Deutsche Krebshilfe e.V., Comprehensive Cancer Center); the Else-Kröner-Fresenius Foundation (R28/09//A46/09); and the DOKTOR ROBERT PFLEGER-STIFTUNG, Bamberg.

  • dx.doi.org/10.1124/pr.113.007518.

  • ↵Embedded ImageThis article has supplemental material available at pharmrev.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 65 (3)
Pharmacological Reviews
Vol. 65, Issue 3
1 Jul 2013
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Review ArticleReview Article

Transporter-Mediated Drug Interactions

Jörg König, Fabian Müller and Martin F. Fromm
Pharmacological Reviews July 1, 2013, 65 (3) 944-966; DOI: https://doi.org/10.1124/pr.113.007518

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Review ArticleReview Article

Transporter-Mediated Drug Interactions

Jörg König, Fabian Müller and Martin F. Fromm
Pharmacological Reviews July 1, 2013, 65 (3) 944-966; DOI: https://doi.org/10.1124/pr.113.007518
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  • Article
    • Abstract
    • I. Introduction
    • II. Expression and General Function of Uptake and Efflux Transporters
    • III. Drug-Drug Interactions
    • IV. Drug-Food Interactions
    • V. Induction of Uptake and Efflux Transporters
    • VI. Genotype-Dependent Drug-Drug Interactions
    • VII. Transporter-Mediated Drug-Drug Interactions in SPCs
    • VIII. Interplay of Drug Transport and Drug Metabolism
    • IX. Conclusions and Outlook
    • Authorship Contributions
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    • Abbreviations
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