The population pharmacokinetics of allopurinol and oxypurinol in patients with gout.

European Journal of Clinical Pharmacology.

Online resource 2

Daniel FB Wright1, Lisa K Stamp2, Tony R Merriman3, Murray L Barclay2,4, Stephen B Duffull1, Nicholas HG Holford5

1School of Pharmacy, University of Otago, Dunedin, New Zealand

2Department of Medicine, University of Otago, Christchurch, New Zealand

3Department of Biochemistry, University of Otago, Dunedin, New Zealand

4Department of Clinical Pharmacology, ChristchurchHospital, Christchurch, New Zealand

5Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand

Genetic variants of several apical and basolateral transporters expressed in the proximal renal tubules were investigated as covariates in the model including the solute carrier proteins SLC22A12 (URAT1), SLC22A11 (OAT4), SLC2A9 (GLUT9) and SLC17A1 (NPT1), the ATP-binding cassette transporter ABCG2 (breast cancer resistant protein) and a scaffolding protein, PDZK1 [25-31]. See table 4 below. These data were collected as part of the ‘Genetics of Gout in Aotearoa’ study which is designed to explore the genetic basis for gout risk [29-31]. All single-nucleotide polymorphisms (SNPs) investigated in this study have been associated either with an increased risk of gout or hyperuricaemia or a protective effect against gout and hyperuricaemia [25-31]. Note that little is known about the transport of oxypurinol in the renal tubules except what can be deduced from drug interaction studies. For the purposes of this analysis we assumed that renal transporters involved in urate transport are also responsible for the renal handling of oxypurinol. In addition, aldehyde oxidase and molybdenum cofactor sulfurase (MOCOS) genotypes were included as covariates. These genotypes were not part of the ‘Genetics of Gout in Aotearoa’ study but were collected and analysed separately on a small group of patients in the Christchurch cohort [32]. AOX1 is the gene that codes aldehyde oxidase, the enzyme believed to account for most of the conversion of allopurinol to oxypurinol [3]. A SNP at c.3404A > G (Asn1135Ser, rs55754655) has been found to predict poor response to azathioprine [33] and therefore may also predict poor response to allopurinol [32]. MOCOS is responsible for the incorporation of a molybdenum cofactor in the purine oxidases, including aldehyde oxidase and xanthine oxidase. Defective enzymes due to MOCOS polymorphisms may therefore alter allopurinol clearance.

The proportion of individuals who were homozygotes for the minor allele for each genetic covariate was relatively small, ranging from 1-15%. For the purposes of this analysis, all individuals with at least one minor allele (both homozygotes and heterozygotes) were considered as a single group. Therefore, for each gene, there were two groups analysed; homozygotes for the major allele, and carriers of at least one minor allele. Individuals with missing genotype information were assigned to the major allele homozygote group. All gene frequencies conformed to the expectations of Hardy–Weinberg equilibrium.

Table S1 (online Resource 2) Details of the genotypic covariates
Gene / Protein / Function / SNP / Base change / Distribution of genotypes (n [%]) / HWEa
P value / Reference
Major allele / Heterozygotes / Minor allele / No data
AOX1 / Aldehyde oxidase (AO) / Purine oxidase / rs55754655 / 3404A > G / AA
40 (38%) / AG
18 (17%) / GG
nil / 46 (44%) / 0.16 / [32,33]
MOCOS / molybdenum cofactor sulfurase / Incorporates molybdenum cofactor in purine oxidases / rs594445 / 2107C > A / CC
33 (32%) / AC
21 (20%) / AA
4 (4%) / 46 (44%) / 0.79 / [32,33]
SLC22A12 / URAT1 / Apical renal transporter / rs3825018 / A>G / AA
33 (32%) / AG
35 (34%) / GG
8 (8%) / 28 (27%) / 0.78 / [25,26]
SLC22A11 / OAT4 / Apical renal transporter / rs17300741 / G>A / GG
18 (17%) / GA
41 (39%) / AA
16 (15%) / 29 (29%) / 0.42 / [27,28]
SLC2A9 / GLUT9 / Apical and basolateral renal transporter / rs11942223 / T > C / TT
65 (63%) / TC
10 (10%) / CC
1 (1%) / 28 (27%) / 0.41 / [29]
SLC17A1 / NPT1 / Apical renal transporter / rs1183201 / T > A / TT
25 (24%) / TA
42 (40%) / AA
8 (8%) / 29 (29%) / 1 / [26,28,30]
ABCG2 / Breast cancer resist protein / Apical renal transporter / rs2231142 / G>T / GG
39 (38%) / GT
30 (29%) / TT
5 (5%) / 30 (29%) / 0.81 / [26,28,31]
PDZK1 / PDZ / Scaffolding protein / rs12129861 / G > A / GG
25 (24%) / GA
33 (32%) / AA
14 (13%) / 32 (31%) / 0.60 / [26,28]
aHWE = Hardy–Weinberg equilibrium