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

AIMS

To study the effect of CYP2C83, the most common CYP2C8 variant allele on the dis-position of (R)-ibuprofen and the association of CYP2C83 with variant CYP2C9 alleles.

METHODS

Three hundred and fifty-five randomly selected Spanish Caucasians were screened for the common CYP2C8 and CYP2C9 mutations. The pharmacokinetics of (R)-ibuprofen were studied in 25 individuals grouped into different CYP2C8 genotypes.

RESULTS

The allele frequency of CYP2C83 (0.17) was found to be higher than that reported for other Caucasian populations (P = 0.0001). The frequencies of CYP2C92 and CYP2C93 were 0.19 (0.16-0.21) and 0.10 (0.08-0.12), respectively. An association between CYP2C83 and CYP2C92 alleles 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 the CYP2C83 allele 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 genotypes CYP2C8*1/1, CYP2C81/3 and CYP2C83/3, 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 variant CYP2C83 alleles was also observed for the area under the concentration-time curve (P < 0.025), and drug clearance (P < 0.03).

CONCLUSION

Polymorphism of the CYP2C8 gene was found to be common, with nearly 30% of the population studied carrying the variant CYP2C8*3 allele. 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.