In vivo and in vitro correlation of microsomal epoxide hydrolase inhibition by progabide

Abstract

Progabide was investigated as a potential inhibitor of microsomal epoxide hydrolase as a result of reports of elevated levels of carbamazepine-10,11-epoxide after coadministration of progabide and carbamazepine to patients with epilepsy. The formation clearance of carbamazepine transdihydrodiol after administration of carbamazepine-10,11-epoxide to healthy volunteers was decreased 26% by progabide. Therapeutic concentrations of progabide inhibited S (+)-styrene oxide hydrolysis in human liver microsomes (inhibition constant [Ki] = 1.9 mumol/L) and purified human liver microsomal epoxide hydrolase (Ki = 4.4 mumol/L). A mixed competitive and noncompetitive mechanism of inhibition best described the effect of progabide on microsomal epoxide hydrolase; the most potent inhibition was competitive. A similar model described the inhibition by the acid metabolite of progabide, although inhibitory concentrations are higher than concentrations observed after progabide therapy. An excellent agreement between the in vivo and in vitro inhibitory potencies of progabide suggests that potential inhibitors of this important detoxification enzyme can be predicted in vitro.