Background/Purpose: Association of ABCG2 Q141K (p.141Lys) with poor urate-lowering response to allopurinol has been reported although the mechanism is unclear. ABCG2 has been reported to be an efflux pump for allopurinol and oxypurinol [1] and for oxypurinol alone [2]. Based on data from the HEK293 cell-line it has been suggested that dysfunctional variants of ABCG2 such as p.141Lys could lead to decreased renal excretion of oxypurinol, higher oxypurinol levels and greater serum urate lowering [2]. To further investigate the apparent inconsistency between ref [2] and association of p.141Lys with poor allopurinol response, we examined the relationship between ABCG2 p.141Lys and plasma oxypurinol.

Methods: We examined, using linear regression, plasma oxypurinol concentrations using participants from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients and Genetics of Gout in Aotearoa studies based on the presence of the ABCG2 p.141Lys.

Results:

Of the 688 individuals, 294 (42.7%) were positive for ≥one p.141Lys allele. In a univariate model plasma oxypurinol concentration was significantly lower in these individuals compared to Gln/Gln homozygotes (mean (SEM) 84.8 (3.6) µmol/l vs. 96.6 (3.1); p=0.013) despite higher allopurinol dose (mean (SD) 326 (101.3) vs. 297 (80.5)mg/d; p<0.001) and higher eGFR (72.7 (24.8) vs 67.5 (22.6) ml/min/1.73m²; p=0.004). Of those in the p.141Lys-positive group, fewer were receiving diuretics compared to the Gln/Gln group (22.4% vs. 31.0%; p=0.08). In a multivariate model that included allopurinol dose, eGFR and the use of diuretics, there was no statistically significant difference between plasma oxypurinol concentrations in the p.141Lys-positive and -negative groups, although levels were numerically lower in the p.141Lys-positive group (97.7 (3.5) µmol/l vs. 104.3 (2.8) µmol/l p=0.12).

Conclusion:

Our results suggest that there are unidentified factors that influence plasma oxypurinol and, despite the evidence presented from the HEK293 cell-line model [2], plasma oxypurinol levels are not significantly different in individuals with the ABCG2 p.141Lys variant. We recommend an individualised dose titration to target serum urate strategy for patients establishing on allopurinol.

1. Wen, C., et al., Genome-wide association study identifies ABCG2 (BCRP) as an allopurinol transporter and a determinant of drug response. Clin Pharm Ther, 2015. 97(5): p. 518-25.
2. Nakamura, M., et al., Investigation of the transport of xanthine oxidase dehydrogenase inhibitors by the urate transporter ABCG2. Drug Metabol Pharmacokinet, 2017. https://doi.org/10.1016/j.dmpk.2017.11.002.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/abcg2-rs2231142-q141k-and-oxypurinol-concentration-in-people-with-gout-receiving-allopurinol/