Pharmacogenetics of Membrane Transporters: An Update on Current Approaches

Abstract

This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.

Pharmacogenetics of Drug Transporters in the Enterohepatic Circulation

“…This has been exemplified in an elegant study for the MDR1 substrate digoxin in humans [45]. MDR1 transports a wide variety of xenobiotics including anticancer drugs, antifungals, antihistamines, antihypertensives, drugs acting in the central nervous system, cardiovascular drugs, HIV-1 protease inhibitors and various immunosuppressants [12,35,43,[46][47][48]. The general theme of MDR1 substrates is that they are structurally unrelated but are either neutral or positively charged hydrophobic compounds.…”

“…has high clinical relevance in drug therapy and the impact of genetic polymorphisms of ABCB1 on drug disposition as well as drug efficacy has been studied extensively and covered in multiple reviews [10,12,[46][47][48][86][87][88][89][90][91][92]. Overall, more than 50 polymorphisms, insertions/deletions and changes in the promoter region have been reported for ABCB1 encoding MDR1 [12,48,93].…”

“…Overall, more than 50 polymorphisms, insertions/deletions and changes in the promoter region have been reported for ABCB1 encoding MDR1 [12,48,93]. A series of nonsynonymous polymorphic variants have been [10,46,48,90,91,97].…”

“…This latter point is illustrated by the observations that Nieman-Pick C1-like 1 protein is located in the apical membrane of enterocytes and involved in cholesterol absorption [5] or that uptake of very long-chain fatty acids into peroxisomes involves the role of the ATP binding cassette (ABC) transporter ABCD1 [6] (see table 1 for a list of transporters and their subcellular expression covered in this review). The number of drug transporters is high and the knowledge on their pharmacogenetics is rapidly evolving [7][8][9][10][11][12][13][14][15].…”

Are ABCB1 (P-glycoprotein) polymorphisms clinically relevant in ovarian cancer? – Finally an Answer!

“…Several of these genetic variants result in alterations in mRNA expression levels (e.g., promoter variants), translational efficiency (e.g., alterations in mRNA folding), and protein function (e.g., coding polymorphisms) [9]. However, there are three singlenucleotide polymorphisms (SNPs) that are common in most ethnic groups: A synonymous transition at nucleotide C1236T (Gly411Gly) (rs1128503) in exon 12, a nonsynonymous transition G2677T/A (Ala893Ser/Thr) (rs2032582) in exon 21, and a synonymous transition C3435T (Ile1145Ile) (rs1045642) in exon 26.…”