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Abstract Number: 1266

ABCG2 rs2231142 Q141K and Oxypurinol Concentration in People with Gout Receiving Allopurinol

Lisa K. Stamp1, Mary Wallace2, Rebecca Roberts3, Christopher Frampton1, Jeffrey Miner4, Tony R. Merriman3 and Nicola Dalbeth5, 1University of Otago, Christchurch, New Zealand, 2Surgical Sciences, University of Otago, Dunedin, New Zealand, 3University of Otago, Dunedin, New Zealand, 4Viscentio Bio, San Diego, CA, 5University of Auckland, Auckland, New Zealand

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Allopurinol and gout

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Session Information

Date: Monday, October 22, 2018

Session Title: Metabolic and Crystal Arthropathies – Basic and Clinical Science Poster I

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

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.

Disclosure: L. K. Stamp, Amgen Inc., 8; M. Wallace, None; R. Roberts, None; C. Frampton, None; J. Miner, None; T. R. Merriman, None; N. Dalbeth, Horizon, 5,Kowa, 5,Amgen Inc., 2,AstraZeneca/Ironwood, 2,AbbVie Inc., 8,Pfizer, Inc., 8,Janssen, 8.

To cite this abstract in AMA style:

Stamp LK, Wallace M, Roberts R, Frampton C, Miner J, Merriman TR, Dalbeth N. ABCG2 rs2231142 Q141K and Oxypurinol Concentration in People with Gout Receiving Allopurinol [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/abcg2-rs2231142-q141k-and-oxypurinol-concentration-in-people-with-gout-receiving-allopurinol/. Accessed March 27, 2023.
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