Mechanism of Carbamazepine Oxidation by CYP3A4

Abstract

CYP3A4 catalyzes 10,11-epoxidation to carbamazepine (CBZ), anti-convulsant drug. This is only one CBZ metabolic route by CYP3A4. However, potential energy of CBZ 10,11-epoxide is about 30 kcal/mol higher than that of hydroxy CBZ. To elucidate the reason why CYP3A4 produces epoxide only in CBZ metabolism, a mechanism of CBZ epoxidation by CYP3A4 was investigated by using theoretical calculations. It was found that the active site of CYP3A4 had geometry to catalyze epoxidation to CBZ and that CBZ 10,11-epoxidation was two-steps reaction proceeding in doublet spin state. The activation energy of the rate-determining step was 13.8 kcal/mol and this reaction can occur in vivo. If hydroxylation mechanism of CBZ by CYP3A4 occurs, the activation energy of the first step reaction is higher than that of the rate-determining step of epoxidation of CBZ by CYP3A4. It is considered that the result explains the reason why 10,11-epoxidation of CBZ is only one CBZ metabolic route by CYP3A4.