Lack of inhibition of clomethiazole metabolism by cimetidine: model experiments in the dog

The disposition of clomethiazole was studied in six dogs subjected to pretreatment with cimetidine or saline according to a cross-over design. Pretreated dogs received approximately 20 mg/kg of cimetidine p.o. for 4 days and 30 mg/kg i.v. immediately before an intraduodenal infusion of clomethiazole (117 mumol/kg clomethiazole base within 90 min). Compared to controls, cimetidine had no effect on peak plasma concentrations and on areas under the plasma concentration time curves of clomethiazole or of its metabolite 5-acetyl-4-methylthiazole (P greater than 0.05). Identical pretreatment of the same dogs resulted in a 50% inhibition of aminopyrine demethylation (P less than 0.001) as revealed by the aminopyrine breath test. Clomethiazole may be metabolized in the dog through metabolic routes which cannot be inhibited by cimetidine.