Feline hepatic biotransformation of diazepam: Differences between cats and dogs

• Hepatic CYP450-mediated biotransformation of diazepam differs between cats and dogs.
• Cats have a limited capacity to glucuronidate diazepam hydroxyl metabolites.
• Feline and canine Bsepareinhibited by diazepam and its metabolites.
• Bsep inhibition leads to accumulation of bile acids, which can lead to liver injury.
• Only use diazepam in cats when there are no alternatives.

In contrast to humans and dogs, diazepam has been reported to induce severe hepatic side effects in cats, particularly after repeated dosing. With the aim to elucidate the mechanisms underlying this apparent sensitivity of cats to drug-induced liver injury, in a series of in vitro experiments, the feline-specific biotransformation of diazepam was studied with liver microsomes obtained from cats and dogs and the possible inhibition of the bile salt export pump (Bsep) was measured in isolated membrane vesicles overexpressing feline and canine Bsep. In line with previous in vivo studies, the phase I metabolites nordiazepam, temazepam and oxazepam were measurable in microsomal incubations, although enzyme velocity of demethylases and hydroxylases differed significantly between cats and dogs. In cats, the main metabolite was temazepam, which also could be glucuronidated. In contrast to dogs, no other glucuronidated metabolites could be observed. In addition, in the membrane vesicles an inhibition of the transport of the Bsep substrate taurocholic acid could be observed in the presence of diazepam and its metabolites. It was concluded that both mechanisms, the slow biotransformation of diazepam as well the inhibition of the bile acid efflux that results in an accumulation of bile acids in the hepatocytes, seem to contribute to the liver injury observed in cats following repetitive treatment with diazepam.