Cytochrome P450 Gene Polymorphisms and Variability in Response to NSAIDs

Abstract

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.