CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers.
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
Department of Pharmacology and Psychiatry, Faculty of Medicine, University of Extremadura, Av. de Elvas s/n, 06071 Badajoz, Spain.
Pedro
P
Dorado
Roland
R
Berecz
Maria-Jesús
MJ
Norberto
Umit
U
Yasar
Marja-Liisa
ML
Dahl
Adrián
A
LLerena
D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000008:administration & dosage / Q000378:metabolism* / Q000652:urine; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D013030:Spain
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases