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CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers

Abstract:

Objective: This study analyzed the frequency of CYP2C9 variant alleles and evaluated the impact of CYP2C9 genotype on diclofenac metabolism in a Spanish population. Methods: Diclofenac hydroxylation capacity was studied in a population of 102 healthy volunteers. After a single oral dose of 50 mg diclofenac the 0- to 8-h urinary concentrations of diclofenac and its main metabolites, 4′-hydroxy (OH), 3′-OH and 5-OH diclofenac were analyzed by high-performance liquid chromatography. CYP2C9 genotyping for the variant alleles CYP2C9*2 and *3 was carried out with PCR-RFLP. Results: The frequencies of CYP2C9*1, *2, and *3 alleles were 0.74 (95%CI: 0.68-0.80), 0.16 (95%CI: 0.11-0.21) and 0.10 (95%CI: 0.06-0.15), respectively, among the 102 Spaniards studied. The diclofenac/4′-OH diclofenac urinary ratio, but not the diclofenac/3′-OH diclofenac and diclofenac/5-OH diclofenac ratios, was related to CYP2C9 genotype. The diclofenac/4′-OH ratio was significantly higher among subjects with CYP2C9*1/*3 (0.83±0.4, n=14, 95% CI for the difference: 0.02-0.4) and CYP2C9*2/*3 (1.10±0.5, n=4, 95% CI for the difference: 0.16-0.8) genotypes compared to CYP2C9*1/*1 (0.62±0.3, n=59) and approximately threefold higher (1.8) in the only subject homozygous for CYP2C9*3 variant. Conclusions: The frequencies of CYP2C9*1, *2, and *3 alleles in the Spanish population reported here were similar to those found in the previously studied white European populations, and different of the previously reported in another Spanish population. CYP2C9*3 allele seems to influence the 4′-hydroxylation of diclofenac, although there is a large overlapping in the urinary metabolic ratio between the genotype groups studied.