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

Abstract

AimsTo study the effect of CYP2C8*3 , the most common CYP2C8 variant allele on the disposition of (R)-ibuprofen and the association of CYP2C8*3 with variant CYP2C9 alleles. MethodsThree 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. ResultsThe allele frequency of CYP2C8 * 3 (0.17) was found to be higher than that reported for other Caucasian populations ( P = 0.0001). The frequencies of CYP2C9 * 2 and CYP2C9 * 3 were 0.19 (0.16-0.21) and 0.10 (0.08-0.12), respectively. An association between CYP2C8 * 3 and CYP2C9 * 2 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 CYP2C8 * 3 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 , CYP2C8 * 1/ * 3 and CYP2C8 * 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 variant CYP2C8 * 3 alleles was also observed for the area under the concentration-time curve ( P < 0.025), and drug clearance ( P < 0.03). ConclusionPolymorphism 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.

Gender and functional CYP2C and NAT2 polymorphisms determine the metabolic profile of metamizole

“…The inferred CYP2C9 phenotype was related to a nearly-significant decrease of the formylated metabolite, as well as a significant decrease in the formylation ratio, among carriers of loss-of function CYP2C9 alleles. Most of this effect is attributable to the variant allele CYP2C9*3, whereas the presence of CYP2C9*2 was related to a weaker effect (see supplemental information Table S6), which is consistent with the weaker impairment in drug metabolism in vivo caused by CYP2C9*2 as compared to CYP2C9*3 [17,[30][31].…”

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…CYP2C9 metabolizes R-and S-ibuprofen in vitro, with R-ibuprofen also being metabolized by CYP2C8. Consistent with this, three human studies showed that ibuprofen concentrations correlate with CYP2C9 genotype (Kirchheiner et al, 2002c;Garcia-Martin et al, 2004;Martinez et al, 2004b). The AUC of racemic ibuprofen was 1.6-and 1.8-fold higher in the *1/*3 and *3/*3 genotypes, due to elevated S-ibuprofen concentrations (1.5-and 1.7-fold, respectively).…”

Cytochrome P450 pharmacogenetics and cancer

“…CYP2C8.3 has been shown to exhibit a lower paclitaxel 6a-hydroxylase activity in heterologous expression systems. However, in vivo the data are contradictory and opposite results have been obtained using different substrates (Dai et al, 2001;Niemi et al, 2003;Martinez et al, 2005). Other variant alleles with missense mutations are CYP2C8*2 and CYP2C8*4, but their impact on enzyme activity is unclear.…”