Sui-Lin Mo, Zhi-Wei Zhou, Li-Ping Yang, Ming Qian Wei and Shu-Feng Zhou Pages 1075 - 1126 ( 52 )
CYP2C9 is one of the most abundant CYP enzymes in the human liver (∼20% of hepatic total CYP content). CYP2C9 metabolizes approximately 20% clinical drugs ( > 120 drugs), including a number of drugs with narrow therapeutic ranges. Some natural compounds are also metabolized, probably leading to the formation of toxic metabolites. CYP2C9 also plays a role in the metabolism of several endogenous compounds such as steroids, melatonin, retinoids and arachidonic acid. Typical substrates of CYP2C9 such as celecoxib, ibuprofen, flurbiprofen, and diclofenac are relatively small, lipophilic and contain acidic groupings with pKa values in the range 3.8—8.1 which will be ionized at physiological pH. The carboxylate groups of tienilic acid and diclofenac have been shown to be responsible for substrate preference and orientation in the active site of CYP2C9. Therefore, a typical CYP2C9 substrate should contain an anionic site and a hydrophobic site. However, neutral or positively charged compounds may also be substrates of CYP2C9. CYP2C9 is subject to inhibition by a number of drugs and other compounds and this may provide an explanation for some clinical drug-drug interactions. With regard to prodrugs that need CYP2C9 for activation, inhibition of CYP2C9 may cause a decrease in the amount of the active metabolite, leading to therapeutic failure. Pharmacophore models have revealed that hydrogen bonding, ion-pair interactions, and probably hydrophobic interactions play a major role in determining the substrate specificity and inhibitor selectivity of CYP2C9. A number of structure-activity relationship studies have identified the structural determinants of compounds for their binding affinity to CYP2C9 and inhibitory potency for CYP2C9. Given the critical role of CYP2C9 in drug metabolism and the presence of polymorphisms, it is important to identify drug candidates as potential substrates and/or inhibitors of CYP2C9 in drug development and drugs with minimal interactions with this enzyme should be chosen for further development. Further studies are warranted to explore the molecular determinants for ligand-CYP2C9 binding and the structure-activity relationships.
CYP2C9, substrate, inhibitor, modeling, pharmacophore, structure-activity relationship
School of Health Sciences&Health Innovations Research Institute, RMIT University, Bundoora, Victoria 3083, Australia.