Inhibitory effect of valproic acid on the disposition of carbamazepine and carbamazepine-10,11-epoxide in the rat.

The effects of valproic acid on the disposition of carbamazepine and carbamazepine epoxide were studied in conscious rats. Each animal received a constant rate infusion of carbamazepine and an iv bolus dose of epoxide in the presence and absence of valproate. The latter was maintained within its therapeutic range by iv infusion. Carbamazepine steady state clearance was decreased by 20.2 +/- 12.7% in the presence of valproate. The formation clearance of carbamazepine epoxide, which accounts for 50% of the total clearance, was decreased on the average by 22.7%. Also, a significant increase in the level of carbamazepine epoxide formed from carbamazepine was found in the presence of valproate. This increase in metabolite level was explained by the large reduction in epoxide clearance (41.6 +/- 13.1%) observed after single doses of epoxide. Based on this finding, a separate study examined the effect of valproate on the non-renal component of the clearance of carbamazepine epoxide. The non-renal clearance of epoxide was decreased by 59.9 +/- 11.9% in the presence of valproic acid.