ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding?

ABSTRACT

Introduction

Interindividual differences in drug response are a frequent clinical challenge partly due to variation in pharmacokinetics. ATP-binding cassette (ABC) transporters are crucial determinants of drug disposition. They are subject of gene regulation and drug-interaction; however, it is still under debate to which extend genetic variants in these transporters contribute to interindividual variability of a wide range of drugs.

Areas covered

This review discusses the current literature on the impact of genetic variants in ABCB1, ABCG2 as well as ABCC1, ABCC2, and ABCC3 on pharmacokinetics and drug response. The aim was to evaluate if results from recent studies would increase the evidence for potential clinically relevant pharmacogenetic effects.

Expert opinion

Although enormous efforts have been made to investigate effects of ABC transporter genotypes on drug pharmacokinetics and response, the majority of studies showed only weak if any associations. Despite few unique results, studies mostly failed to confirm earlier findings or still remained inconsistent. The impact of genetic variants on drug bioavailability is only minor and other factors regulating the transporter expression and function seem to be more critical. In our opinion, the findings on the so far investigated genetic variants in ABC efflux transporters are not suitable as predictive biomarkers.

KEYWORDS:

• ATP-binding cassette transporters
• pharmacokinetics
• pharmacogenetics
• drug response
• drug resistance

Article highlights

• Inconsistency or lack of association make ABCB1 variants not suitable as predictive genetic biomarkers for dose optimization of ABCB1 substrates in pharmacogenetics-based clinical decision support.

• For ABCG2, the variant 421C>A (Q141K) was demonstrated to affect the bioavailability of statins such as rosuvastatin, however, it has not been proven as predictive biomarker for statin response so far.

• ABCC2 genetic variants might have a some impact on the pharmacokinetics of drugs as methotrexate and atorvastatin, however without significant proof of relevant clinical consequences.

• Current data do not provide enough evidence to recommend genotyping of ABC efflux transporter as predictive biomarker for drug bioavailability or drug response.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.