Repeated dosing of diazepam in cats is associated with severe acute liver injury, which is demonstrated by centrilobular hepatic necrosis, biliary duct proliferation and hyperplasia, and suppurative intraductal inflammation. Affected cats may appear depressed and be anorexic and icteric.
This study investigated possible mechanisms for diazepam sensitivity in cats. To determine if diazepam is metabolized differently in cats than in dogs, canine and feline microsomes were incubated with diazepam to compare biotransformation. The predominate metabolite found in cats (temazepam) was different than that found in dogs (nordiazepam and oxazepam) and was produced at a lower efficiency. The authors attributed this finding to enzyme characteristics that differ from humans and dogs as well as to the lower glucuronidation capacity of diazepam hydroxylate metabolites in cats.
Transport studies were then performed by isolation of membrane vesicles to determine if diazepam or its metabolites inhibit the bile salt export pump and cause accumulation of bile acids in hepatocytes. A slightly higher inhibitory effect of diazepam and its metabolites on bile salt export pump transport activity was found in cats as compared with dogs.
The authors concluded that both slow diazepam biotransformation and inhibition of bile acid efflux contribute to diazepam-induced liver injury in cats. The authors suggested amending the diazepam dose and dosing interval in cats and recommended continued research into specific drug biotransformation and transport mechanisms in cats for individual drugs.