Inhibition of epoxidation of carbamazepine by valproic acid in the isolated perfused rat liver

The effect of valproic acid on carbamazepine epoxidation in the perfused liver was investigated in two separate studies. In study I, significant decreases were observed both in the intrinsic clearance of carbamazepine and the intrinsic formation clearance of carbamazepineepoxide in the presence of therapeutic concentrations of valproate. The same inhibitory effect of valproate was also observed in liver preparations from a group of animals pretreated with carbamazepine. Study II focused on the effect of valproate and carbamazepine on the apparent Michaelis-Menten parameters (V_max,m,K_m,m)associated with the intrinsic formation clearance of carbamazepineepoxide in the perfused liver. Valproate had no statistically significant effect on either the V_max,morthe K_m,mof epoxidation, although the K_m,mvalue was 43% higher in the presence of valproate. However, the ratio of V_max,mand K_m,m(intrinsic formation clearance) was significantly reduced by valproate. The V_max,mand K_m,mvalues obtained in study II predicted a significant decrease in the intrinsic formation clearance of carbamazepineepoxide, consistent with the results of study I. Carbamazepine pretreatment was associated with significant increases in apparent V_max,mand K_m,mof epoxide formation.This work was supported in part by NINCDS research grant NS-04053 and NIGMS research grant l P01 GM32165-01.