ABSTRACT
Carbamazepine (CBZ) is a commonly prescribed antiepileptic drug, and is mainly metabolized to 10,11-CBZ epoxide in humans. Its biotransformation is catalyzed by cytochrome P450 (CYP) enzymes, with the predominant isoforms being CYP3A4 and CYP3A5. In the present study, the effects of the CYP3A5*3 (rs776746) polymorphism on CBZ 10,11-epoxidation in human liver microsomes genotyped as CYP3A5*3 were examined using a kinetic analysis. The kinetics for CBZ 10,11-epoxidation fit the Hill model with n of approximately 1.9-2.1 in all liver microsomes of the wild-type (CYP3A5*1/*1) and heterozygous (CYP3A5*1/*3) and homozygous (CYP3A5*3/*3) variants. The S50, Vmax, and CLmax values of wild-type liver microsomes were 263-327 µM, 793-1590 pmol/min/mg protein, and 1.51-2.95 µL/min/mg protein, respectively. The Vmax and CLmax values of liver microsomes of the heterozygous variant were approximately 15-40% those of wild-type liver microsomes. On the other hand, the Vmax and CLmax values of liver microsomes of the homozygous variant were more similar to those of the wild-type than the heterozygous variant. These results suggest that the CYP3A5*3 polymorphism has a negligible effect on CBZ 10,11-epoxidation in an in vitro system using human liver microsomes.