Polymorphisms of the drug transporters ABCB1, ABCG2, ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance

Abstract

Introduction: Human ATP-binding cassette (ABC) transporters act as translocators of numerous substrates across extracellular and intracellular membranes, thereby contributing to bioavailability and consequently therapy response. Genetic polymorphisms are considered as critical determinants of expression level or activity and subsequently response to selected drugs.

Areas covered: Here the influence of polymorphisms of the prominent ABC transporters P-glycoprotein (MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2) and the multidrug resistance-associated protein (MRP) 2 (ABCC2) as well as MRP3 (ABCC3) on the pharmacokinetic of drugs and associated consequences on therapy response and clinical outcome is discussed.

Expert opinion: ABC transporter genetic variants were assumed to affect interindividual differences in pharmacokinetics and subsequently clinical response. However, decades of medical research have not yielded in distinct and unconfined reproducible outcomes. Despite some unique results, the majority were inconsistent and dependent on the analyzed cohort or study design. Therefore, variability of bioavailability and drug response may be attributed only by a small amount to polymorphisms in transporter genes, whereas transcriptional regulation or post-transcriptional modification seems to be more critical. In our opinion, currently identified genetic variants of ABC efflux transporters can give some hints on the role of transporters at interfaces but are less suitable as biomarkers to predict therapeutic outcome.

Keywords: ATP-binding cassette transporters; drug response; efflux transporter; multidrug resistance; pharmacogenetics; pharmacokinetics; transmembranal transport.