Effect of route of administration on the pharmacokinetics and toxicokinetics of cinnarizine in dogs

Abstract

Aims: Cinnarizine, a piperazine derivative, is currently used for the treatment of cerebral thrombosis, cerebral arteriosclerosis, subarachnoid hemorrhage and some other diseases. However, it exhibits variable dissolution and low bioavailability after oral administration. Cinnarizine for injection was developed in order to enhance its bioavailability and make the practice more convenient for patients suffering from dysphagia. The aim of the present study was to compare the pharmacokinetics and toxicokinetics of cinnarizine following intravenous and oral administration in dogs and provide scientific basis for the development of cinnarizine for injection.

Methods: Beagle dogs were given single- or multiple-dose of cinnarizine by oral (single-dose: 10mg/kg; multiple-dose: 21.5, 12.9, 4.3mg/kg) and intravenous (single-dose: 10mg/kg; multiple-dose: 10, 6, 2mg/kg) routes. HPLC was applied to detect the plasma concentration of cinnarizine. The pharmacokinetics and toxicokinetics parameters were calculated and compared.

Results: The pharmacokinetics of cinnarizine following oral administration in dogs was found to fit the one-compartment mode. That of cinnarizine following intravenous injection in dogs was found to fit the two-compartment model. The relative bioavailability of oral administration was 46.4%. Cinnarizine cumulated significantly in dogs when 10mg/kg cinnarizine was injected repeatedly. Multiple-dose of cinnarizine over 6mg/kg induced reversible kidney injury in dogs.

Conclusion: The present study indicates that pharmacokinetics and toxicokinetics properties of cinnarizine for injection show advantages over the oral preparation. But caution should be taken with the cumulative action when cinnarizine is injected and the dose of cinnarizine should be lower than 6mg/kg.