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 carbamazepine-epoxide 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 (Vmax,m, Km,m) associated with the intrinsic formation clearance of carbamazepine-epoxide in the perfused liver. Valproate had no statistically significant effect on either the Vmax,m or the Km,m of epoxidation, although the Km,m value was 43% higher in the presence of valproate. However, the ratio of Vmax,m and Km,m (intrinsic formation clearance) was significantly reduced by valproate. The Vmax,m and Km,m values obtained in study II predicted a significant decrease in the intrinsic formation clearance of carbamazepine-epoxide, consistent with the results of study I. Carbamazepine pretreatment was associated with significant increases in apparent Vmax,m and Km,m of epoxide formation.