Pharmacogenetics of Membrane Transporters A Review of Current Approaches

Tristan M. Sissung, Erin R. Gardner, Rui Gao, and William D. Figg

Summary This chapter provides a review of the pharmacogenetics of membrane transporters, including adenosine triphosphate-binding cassette (ABC) transporters and organic anion transporting proteins (OATPs). Membrane transporters are heavily involved in drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have a significant effect on the absorption, distribution, metabolism, and excretion of compounds. The techniques used to identify substrates and inhibitors of these proteins and subsequently assess the effect of genetic mutation on transport, both in vitro and in vivo, are outlined and discussed. Finally, studies linking transporter genotype with clinical outcomes are discussed.

Keywords ABCB1; ABCC1; ABCC2; ABCG2; OATP1B1; OATP1B3; polymorphisms; transport.

4.1 Introduction

The fate of a drug in vivo is dictated by a variety of physiochemical properties, including size, lipophilicity, and charge. These properties determine how a drug is absorbed into the blood, distributed throughout the body, metabolized, and eventually eliminated. While movement of a drug molecule can occur through simple diffusion, there are many transporter proteins expressed on cell membranes to assist

4.1 Introduction

4.2 Genetic Variation and Genotyping Methods

4.3 Substrate Identification

4.4 Assessing Functional Significance of Polymorphisms In Vitro

4.5 Assessing Functional Significance of Polymorphisms In Vivo .

4.6 Transporter Genetics in Clinical Pharmacology

4.7 Transporter Genetics in Clinical Endpoint Analysis


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