Inhibition of carbamazepine metabolism by cimetidine

The effect of cimetidine on the single dose pharmacokinetics of carbamazepine was examined in nine male Sprague-Dawley rats after the administration of a 25 mg/kg iv dose of carbamazepine. Five rats received a concomitant 50 mg/kg iv dose of cimetidine. Concomitant cimetidine administration produced a decrease in carbamazepine clearance (liters/hr/kg) (0.68 +/- 0.037 vs. 0.41 +/- 0.091; p less than 0.002) which was accompanied by an increase in carbamazepine half-life (hr) (1.1 +/- 0.16 vs. 2.0 +/- 0.37; p less than 0.003). No cimetidine-induced alterations in the volume of distribution at steady-state (liters/kg) occurred (1.1 +/- 0.14 vs. 1.2 +/- 0.04; NS). A reduction in the partial area under the plasma concentration-time curve for carbamazepine-10, 11-epoxide (mg X hr/liter) (28 +/- 2.5 vs. 18 +/- 3.7; p less than 0.002) with cimetidine treatment suggests that a portion of the reduction in carbamazepine clearance may be the result of cimetidine-induced inhibition of epoxide formation. The effect of cimetidine on epoxide formation was further substantiated using an in vitro rat liver homogenate preparation where inhibition of epoxide formation by cimetidine occurred in a dose-dependent fashion.