ABSTRACT
Introduction
In addition to the well-established understanding of the pharmacogenetics of drug-metabolizing enzymes, there is growing data on the effects of genetic variation in drug transporters, particularly ATP-binding cassette (ABC) transporters. However, the evidence that these genetic variants can be used to predict drug effects and to adjust individual dosing to avoid adverse events is still limited.
Areas covered
This review presents a summary of the current literature from the PubMed database as of February 2024 regarding the impact of genetic variants on ABCG2 function and their relevance to the clinical use of the HMG-CoA reductase inhibitor rosuvastatin and the xanthine oxidase inhibitor allopurinol.
Expert opinion
Although there are pharmacogenetic guidelines for the ABCG2 missense variant Q141K, there is still some conflicting data regarding the clinical benefits of these recommendations. Some caution appears to be warranted in homozygous ABCG2 Q141K carriers when rosuvastatin is administered at higher doses and such information is already included in the drug label. The benefit of dose adaption to lower possible side effects needs to be evaluated in prospective clinical studies.
Article highlights
The relevance of single nucleotide variants (SNVs) of the ATP-binding cassette transporter ABCG2 for clinical practice is currently the subject of various clinical studies with partly conflicting data.
ABCG2 V12M (rs2231137) and Q141K (rs2231142) are the most studied variants. Whereas Q141K was shown to lead to reduced protein expression and transport activity, V12M does not appear to affect expression or functionality.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) have both published guidelines considering ABCG2.
The CPIC guideline on rosuvastatin suggests an initial dose of ≤20 mg of the HMG-CoA reductase inhibitor for patients being homozygous for ABCG2 Q141K due to an increased risk for statin-associated musculoskeletal symptoms (SAMS).
The DPWG guideline recommends a 1.25-fold higher dose of the xanthine oxidase inhibitor allopurinol for heterozygous Q141K carriers and a 1.4-fold higher dose for homozygous Q141K carriers due to an observed association of this variant with decreased allopurinol efficacy.
Overall, based on the current literature ABCG2 Q141K moderately affects rosuvastatin plasma concentrations and is considered to be related to statin-associated muscle symptoms. Confirmation on the benefit of dose-adaption based on real-world data, however, is so far pending. The association of Q141K on allopurinol bioavailability remains to be further elucidated as there is conflicting data.
List of abbreviations
ABC transporter: ATP-binding cassette (ABC) transporters; ALL: all populations; ATP: adenosine triphosphate; ATPase: adenosine triphosphatase; AUC: area under the curve; BCRP: breast cancer resistance protein; CK: creatine kinase; CML: chronic myeloid leukemia; CPIC: Clinical Pharmacogenetics Implementation Consortium; Cryo-EM: Cryo-electron microscopy; CYP enzymes: cytochrome P450; DPWG: Dutch pharmacogenetics working group; EMA: European Medicines Agency; ER: endoplasmic reticulum; FDA: United States Food and Drug Administration; GWAS: genome-wide association study; HLA: human leukocyte antigen; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; HNF4A: hepatocyte nuclear factor 4 alpha; LDL: low-density lipoprotein; MAF: minor allele frequency; MDR1: multidrug resistance protein 1; mRNA: messenger RNA; MRP1: multidrug resistance-associated protein 1; N/A: not available; NBD: nucleotide-binding domain; PD: pharmacodynamics; P-gp: P-glycoprotein; PK: pharmacokinetics; RNA: ribonucleic acid; SAMS: statin-associated muscle symptoms; SCAR: severe cutaneous adverse reaction; SJS: Steven-Johnson syndrome; SNP: single nucleotide polymorphism; SNV: single nucleotide variant; SPC: summary of product characteristics; TEN: toxic epidermal necrolysis; TKI: tyrosine kinase inhibitors; TMD: transmembrane domain; UK: United Kingdom.
Declaration of interests
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.