The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects.

To study the effect ofCYP2C8*3, the most commonCYP2C8variant allele on the dis-position of (R)-ibuprofen and the association of CYP2C8*3 with variantCYP2C9alleles.Three hundred and fifty-five randomly selected Spanish Caucasians were screened for the commonCYP2C8andCYP2C9mutations. The pharmacokinetics of (R)-ibuprofen were studied in 25 individuals grouped into differentCYP2C8genotypes.The allele frequency ofCYP2C8* 3(0.17) was found to be higher than that reported for other Caucasian populations (P = 0.0001). The frequencies ofCYP2C9* 2andCYP2C9* 3were 0.19 (0.16–0.21) and 0.10 (0.08–0.12), respectively. An association betweenCYP2C8* 3andCYP2C9* 2alleles was observed, occurring together at a frequency 2.4-fold higher than expected for a random association of alleles (P = 0.0001). The presence of theCYP2C8* 3allele was found to influence the pharmacokinetics of (R)-ibuprofen in a gene–dose effect manner. Thus, after administration of 400 mg ibuprofen, the plasma half-life (95% confidence intervals) for individuals with genotypesCYP2C8* 1/* 1,CYP2C8* 1/* 3andCYP2C8* 3/* 3, was 2.0 h (1.8–2.2), 4.2 h (1.9–6.5;P < 0.05) and 9.0 h (7.8–10.2;P < 0.002), respectively. A statistically significant trend with respect to the number of variantCYP2C8* 3alleles was also observed for the area under the concentration-time curve (P < 0.025), and drug clearance (P < 0.03).Polymorphism of theCYP2C8gene was found to be common, with nearly 30% of the population studied carrying the variantCYP2C8* 3allele. The presence of the latter caused a significant effect on the disposition of (R)-ibuprofen. This suggests that a substantial proportion of Caucasian subjects may show alterations in the disposition of drugs that are CYP2C8 substrates. [ABSTRACT FROM AUTHOR]