Cimetidine interaction with dipotassium clorazepate disposition in the anesthetized dog

Cimetidine (CIM) was used as an interacting agent on the disposition in dogs of dipotassium clorazepate ( CZP ) and its main metabolite nordiazepam (ND) in order to study some of the factors contributing to pharmacokinetic interspecies variation of benzodiazepines in dogs and man. A 0.5 mg/kg of body weight intravenous (i.v.) bolus dose of CZP was administered to 12 anesthetized mongrel dogs, 6 of them receiving also, 30 min before, a 1 mg/kg i.v. bolus dose of CIM followed by a constant i.v. infusion (1 mg/kg/hr) of CIM. Plasma ND and CZP concentrations were measured as a function of time with an high-performance liquid chromatography method. Plasma levels of CZP declined mono- and biexponentially in 1 and 5 dogs, respectively, for each group of animals. No statistically significant difference was found between CZP pharmacokinetic parameters when the 2 groups of dogs were compared. However, a 37% decrease in ND beta half-life, t1/2 beta, when CZP was associated with CIM, was found to be statistically significant. The i.v. administration of pure ND in two dogs, has shown that ND declines biexponentially with a t1/2 beta similar to the one estimated after CZP dosing in control animals. The hepatic metabolism of ND was found to be flow-independent and restrictive. The data, along with previously reported CIM interactions, suggest that several factors, which would be species-dependent, must be responsible of CIM effect on other drugs.