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Nonsteroidal antiinflammatory drugs (NSAIDs) are often metabolized by enzymes of the cytochrome P450 2C (CYP2C) family, CYP2C9 being the main enzyme involved in the biodisposition of these drugs. In the last decade, extensive research was conducted to identify the effect of polymorphism on the CYP2C9 gene in drug metabolism, and in the development of adverse effects after NSAIDs use. Here we review the findings obtained in these studies, with special focus on the relative importance of CYP2C9 in the metabolism and side effects of diverse NSAIDS, including aceclofenac, aspirin, celecoxib, diclofenac, dipyrone, flurbiprofen, ibuprofen, indomethacin, lornoxicam, meloxicam, naproxen, parecoxib, piroxicam, tenoxicam and valdecoxib. The role of the variant alleles CYP2C9*2, CYP2C9*3 and CYP2C8*3 in the metabolism in vivo and in vitro of these drugs is summarized, and key points that require further investigation are identified. The available information indicates that studies on these topics are still far from being completed. Remaining open questions include the putative role of major CYP2C8 and some recently identified CYP2C9 variant alleles, which is unknown for most NSAIDs, as well as the effect of common CYP2C9 variant alleles in the pharmacokinetics of most NSAIDs. In addition, the relative importance of further studies on the role of CYP2C genotypes with adverse reactions and other major issues to be investigated for NSAIDs known to be CYP2C8 and/or CYP2C9 substrates is outlined. [ABSTRACT FROM AUTHOR]

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]

Impaired drug metabolism is a major cause of adverse drug reactions, and it is often caused by mutations at genes coding for drug-metabolising enzymes. Two amino-acid polymorphisms of cytochrome P4502C9 (CYP2C9), an enzyme involved in the metabolism of several nonsteroidal anti-inflammatory drugs (NSAIDs), were studied in 94 individuals with acute bleeding after NSAIDs use and 124 individuals receiving NSAIDs with no adverse effects. The frequency of CYP2C9 variant alleles was increased in overall bleeding patients, with a significant trend to higher risk with increasing number of variant alleles (P=0.02). The odds ratio for bleeding patients receiving CYP2C9 substrates (n=33) was 2.5 for heterozygous and 3.7 for homozygous carriers of mutations (P<0.015), suggesting that the inherited impairment of CYP2C9 activity increases the risk for severe adverse drug reactions after NSAIDs use.British Journal of Pharmacology (2004) 141, 205-208. doi:10.1038/sj.bjp.0705623 [ABSTRACT FROM AUTHOR]