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Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature

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Abstract

ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

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Acknowledgments

This work was supported by the German Federal Ministry of Education and Research (Virtual Liver Network Grant No. 2318 0315755 and Grant No. 03 IS 2061C), Deutsche Forschungsgemeinschaft KFO 274 (Grant No. SCHW858/1-1), Robert Bosch Stiftung, Stuttgart, Germany, and a University of Tübingen—Faculty of Medicine PATE grant (Project No. F1315013).

SW, ES, HL, MS and ATN have no conflicts of interest.

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  1. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hoppe-Seyler Strasse 3, 72076, Tübingen, Germany

    Stefan Wolking & Holger Lerche

  2. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstr. 112, 70376, Stuttgart, Germany

    Elke Schaeffeler, Matthias Schwab & Anne T. Nies

  3. University of Tübingen, Tübingen, Germany

    Elke Schaeffeler & Anne T. Nies

  4. Department of Clinical Pharmacology, University Hospital Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany

    Matthias Schwab

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  1. Stefan Wolking
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  2. Elke Schaeffeler
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Correspondence to Matthias Schwab.

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Wolking, S., Schaeffeler, E., Lerche, H. et al. Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature. Clin Pharmacokinet 54, 709–735 (2015). https://doi.org/10.1007/s40262-015-0267-1

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