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The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics.
Clin Transl Sci. 2023 Mar; 16(3):422-428.CT

Abstract

The genetic determinants of the allopurinol dose-concentration relationship have not been extensively studied. We aimed to clarify what factors, including genetic variation in urate transporters, influence oxypurinol pharmacokinetics (PKs). A population PK model for oxypurinol was developed with NONMEM (version 7.3). The influence of urate transporter genetic variants for ABCG2 (rs2231142 and rs10011796), SLC2A9/GLUT9 (rs11942223), SLC17A1/NPT1 (rs1183201), SLC22A12/URAT1 (rs3825018), SLC22A11/OAT4 (rs17300741), and ABCC4/MRP4 (rs4148500), as well as other participant factors on oxypurinol PKs was assessed. Data from 325 people with gout were available. The presence of the T allele for ABCG2 (rs2231142) and SLC17A1/NPT1 (rs1183201) was associated with a 24% and 22% increase in oxypurinol clearance, respectively, in univariate analysis. This effect was not significant in the multivariate analysis. In the final model, oxypurinol PKs were predicted by creatinine clearance, diuretic use, ethnicity, and body weight. We have found that genetic variability in the transporters examined does not appear to influence oxypurinol PKs.

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Authors+Show Affiliations

Hishe HZ
School of Pharmacy, University of Otago, Dunedin, New Zealand. School of Pharmacy, Mekelle University, Mekelle, Tigray, Ethiopia.
Stocker SL
School of Pharmacy, University of Sydney, New South Wales, Sydney, Australia. Department of Clinical Pharmacology & Toxicology, St. Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia.
Stamp LK
Department of Medicine, University of Otago, Christchurch, New Zealand.
Dalbeth N
Department of Medicine, University of Auckland, Auckland, New Zealand.
Merriman TR
Department of Biochemistry, University of Otago, Dunedin, New Zealand. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Phipps-Green A
Department of Biochemistry, University of Otago, Dunedin, New Zealand.
Wright DFB
School of Pharmacy, University of Otago, Dunedin, New Zealand.

MeSH

HumansOxypurinolUric AcidGoutAllopurinolOrganic Anion TransportersOrganic Cation Transport ProteinsGlucose Transport Proteins, Facilitative

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

36398357

Citation

Hishe, Hailemichael Z., et al. "The Impact of Genetic Variability in Urate Transporters On Oxypurinol Pharmacokinetics." Clinical and Translational Science, vol. 16, no. 3, 2023, pp. 422-428.
Hishe HZ, Stocker SL, Stamp LK, et al. The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics. Clin Transl Sci. 2023;16(3):422-428.
Hishe, H. Z., Stocker, S. L., Stamp, L. K., Dalbeth, N., Merriman, T. R., Phipps-Green, A., & Wright, D. F. B. (2023). The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics. Clinical and Translational Science, 16(3), 422-428. https://doi.org/10.1111/cts.13460
Hishe HZ, et al. The Impact of Genetic Variability in Urate Transporters On Oxypurinol Pharmacokinetics. Clin Transl Sci. 2023;16(3):422-428. PubMed PMID: 36398357.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The impact of genetic variability in urate transporters on oxypurinol pharmacokinetics. AU - Hishe,Hailemichael Z, AU - Stocker,Sophie L, AU - Stamp,Lisa K, AU - Dalbeth,Nicola, AU - Merriman,Tony R, AU - Phipps-Green,Amanda, AU - Wright,Daniel F B, Y1 - 2022/11/25/ PY - 2022/11/2/revised PY - 2022/10/1/received PY - 2022/11/8/accepted PY - 2022/11/19/pubmed PY - 2023/3/17/medline PY - 2022/11/18/entrez SP - 422 EP - 428 JF - Clinical and translational science JO - Clin Transl Sci VL - 16 IS - 3 N2 - The genetic determinants of the allopurinol dose-concentration relationship have not been extensively studied. We aimed to clarify what factors, including genetic variation in urate transporters, influence oxypurinol pharmacokinetics (PKs). A population PK model for oxypurinol was developed with NONMEM (version 7.3). The influence of urate transporter genetic variants for ABCG2 (rs2231142 and rs10011796), SLC2A9/GLUT9 (rs11942223), SLC17A1/NPT1 (rs1183201), SLC22A12/URAT1 (rs3825018), SLC22A11/OAT4 (rs17300741), and ABCC4/MRP4 (rs4148500), as well as other participant factors on oxypurinol PKs was assessed. Data from 325 people with gout were available. The presence of the T allele for ABCG2 (rs2231142) and SLC17A1/NPT1 (rs1183201) was associated with a 24% and 22% increase in oxypurinol clearance, respectively, in univariate analysis. This effect was not significant in the multivariate analysis. In the final model, oxypurinol PKs were predicted by creatinine clearance, diuretic use, ethnicity, and body weight. We have found that genetic variability in the transporters examined does not appear to influence oxypurinol PKs. SN - 1752-8062 UR - https://www.unboundmedicine.com/medline/citation/36398357/The_impact_of_genetic_variability_in_urate_transporters_on_oxypurinol_pharmacokinetics_ DB - PRIME DP - Unbound Medicine ER -