Interaction of Cimetidine and Ranitidine, the H₂-Receptor Blockers, with Mexazolam, a Benzodiazepinooxazole-Anxiolytic in Rats

Abstract

Mexazolam, a benzodiazepinooxazole-anxiolytic, was first N-dealkylated to M₁ and then hydroxylated to lorazepam in rat liver microsomes. The production of M₁ in vitro was inhibited by SKF-525 A, carbon monoxide and in the atmosphere of nitrogen. The heat-treated microsomes, the omission of an NADPH-generating system and the substitution of NADPH with NADH showed practically no activity. The microsomes obtained from the phenobarbital treated rats showed increased activity toward both the production of M₁ and lorazepam from mexazolam, but the clofibrate and 3-methylcholanthrene treatments failed to induce this activity. Cimetidine inhibited non-competitively both steps in the metabolism of mexazolam: mexazolam to M₁ (K_i: 375 μM) and M₁ to lorazepam (K_i: 390 μM). Ranitidine did not inhibit in vitro metabolism of mexazolam at the concentrations so far investigated ( ?? 400 μM). The pretreatment of rats with cimetidine (200 mg/kg, i.p.) 30 min prior to the administration of mexazolam (50 mg/kg, i.p.), increased AUC and the plasma half-life of mexazolam 8.8-fold and 7.7-fold, respectively. On the other hand, the co-administration of ranitidine did not change the pharmacokinetic parameters of mexazolam.