Effects of CYP2C9*3 and CYP2C9*13 on Diclofenac Metabolism and Inhibition-based Drug-Drug Interactions.
Cytochrome P450 2C9 (CYP2C9) is a polymorphic enzyme responsible for the metabolism of many important drugs, including diclofenac. CYP2C9*3 and CYP2C9*13 are the principal variant alleles found in the Chinese population. CYP2C9*3 has been reported to reduce the metabolism of diclofenac and alter the extent of drug-drug interactions (DDIs). The effects of CYP2C9*13 on diclofenac metabolism are not well studied, and the influences of CYP2C9*13 on DDIs between diclofenac and clinical drugs are still unknown. In this study, CYP2C9.1 (the wildtype enzyme), CYP2C9.3 and CYP2C9.13 were expressed in yeast, and their metabolic kinetics for diclofenac 4'-hydroxylation were examined. From the in vitro data, we predicted a decrease in the ratio of diclofenac oral clearance (the ratio of oral clearance in subjects with variant CYP2C9 alleles to that in wildtype subjects (CL(oral)R)) in subjects carrying CYP2C9*3 or CYP2C9*13 alleles. Furthermore, we investigated the effects of these two alleles on diclofenac-drug interactions. The potentials of nine clinically used drugs to inhibit diclofenac 4'-hydroxylation catalyzed by the alleles were compared. Our results indicated that CYP2C9.3 and CYP2C9.13 can alter the CYP-inhibitory potencies of some tested drugs. In particular, CYP2C9.13 significantly weakened the inhibitory potencies of sulfaphenazole, fluvastatin, fluvoxamine and tranylcypromine. These data provide helpful guidelines for co-administration of diclofenac with other drugs in individuals carrying CYP2C9*3 and CYP2C9*13 alleles.
Zi
Jing
J
National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, Xi'an, China.
Liu
Duan
D
Ma
Pingping
P
Huang
He
H
Zhu
Juanli
J
Wei
Dongqing
D
Yang
Jin
J
Chen
Chao
C
D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D065729:Cytochrome P-450 CYP2C9; D004008:Diclofenac / Q000378:metabolism*; D004347:Drug Interactions; D006801:Humans; D008657:Metabolic Clearance Rate; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D011994:Recombinant Proteins; D004008:Diclofenac; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases