An association study of ABCG2 rs2231142 on the concentrations of allopurinol and its metabolites

Abstract

ABCG2 is a gene that codes for the human breast cancer resistance protein (BCRP). It is established that rs2231142 G>T, a single nucleotide polymorphism of the ABCG2 gene, is associated with gout and poor response to allopurinol, a uric acid‐lowering agent used to treat this condition. It has also been suggested that oxypurinol, the primary active metabolite of allopurinol, is a substrate of the BCRP. We thus hypothesized that carrying the rs2231142 variant would be associated with decreased oxypurinol concentrations, which would explain the lower reduction in uric acid. We performed a cross‐sectional study to investigate the association between the ABCG2 rs2231142 variant and oxypurinol, allopurinol, and allopurinol riboside concentrations in 459 participants from the Montreal Heart Institute Hospital Cohort. Age, sex, weight, use of diuretics, and estimated glomerular filtration rate were all significantly associated with oxypurinol plasma concentration. No association was found between rs2231142 and oxypurinol, allopurinol and allopurinol riboside plasma concentrations. Rs2231142 was not significantly associated with daily allopurinol dose in the overall population, but an association was observed in men, with T carriers receiving higher doses. Our results do not support a major role of ABCG2 in the pharmacokinetics of allopurinol or its metabolites. The underlying mechanism of the association between rs2231142 and allopurinol efficacy requires further investigation.

The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics

“…By extension, these findings suggest that carriers of the T allele, taking the same dose as those without the T allele, would be expected to have increased urate-lowering response, rather than the reduced response noted in other work. 3,[20][21][22][23][24] By contrast, some studies 8,21,25 have not found a relationship between ABCG2 genotype and oxypurinol PKs. The results of our study suggest that the reported association between ABCG2 genotype and allopurinol treatment response is not the result of altered oxypurinol PKs and may reflect alterations in urate disposition.…”

Females present higher dose‐adjusted drug concentrations of metoprolol and allopurinol/oxypurinol than males

“…The selection of individuals was previously reported 15,16 . Succinctly, the two studies included self‐reported “White” males and females aged ≥18 years.…”

Cannabis Pharmacogenomics: A Path to Personalized Medicine

“…The effect of the ABCG2 gene polymorphisms on the pharmacokinetics of multiple drugs has been demonstrated [ 345 , 346 ]. Upregulated ABCG2 expression leads to a reduction in the drug plasma concentrations [ 347 , 348 , 349 ], while the downregulation and/or reduced-of-function variations tend to produce higher drug levels [ 345 , 350 , 351 ].…”

“…The T carriers of Q141K were linked to high risk of gout and reduced response to gout treatment by allopurinol [ 359 , 360 ]. However, recent studies have found no association between rs2231142 and oxypurinol, or allopurinol riboside plasma concentrations [ 346 , 361 ]. In other studies, the T carriers not only produced high concentrations of other BCRP substrates such as rosuvastatin and imatinib, but also generated a greater therapeutic effect of the drugs [ 345 , 346 , 362 , 363 , 364 , 365 ].…”

“…However, recent studies have found no association between rs2231142 and oxypurinol, or allopurinol riboside plasma concentrations [ 346 , 361 ]. In other studies, the T carriers not only produced high concentrations of other BCRP substrates such as rosuvastatin and imatinib, but also generated a greater therapeutic effect of the drugs [ 345 , 346 , 362 , 363 , 364 , 365 ]. Moreover, the SNP C421A may influence the susceptibility to cancer development, survival, and treatment outcomes [ 366 , 367 , 368 , 369 ].…”