Feline hepatic biotransformation of diazepam: Differences between cats and dogs.

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.

Spinosad is a potent inhibitor of canine P-glycoprotein.

Inhibition of the drug transporter P-glycoprotein (P-gp) by the oral flea preventative spinosad has been suggested as the underlying cause of the drug-drug interaction with ivermectin. In this study, an in vitro model consisting of canine cells was validated to describe the inhibitory effect of drugs on canine P-gp. In this model, ivermectin, cyclosporin, verapamil, loperamide and ketoconazole inhibited P-gp function with IC50 values ranging from 0.

The feline bile salt export pump: a structural and functional comparison with canine and human Bsep/BSEP.

Background: The bile salt export pump (BSEP/ABCB11) is the primary transporter for the excretion of bile acids from hepatocytes into bile. In human, inhibition of BSEP by drugs has been related to drug-induced cholestasis and subsequent cytotoxic effects. The role of BSEP in canine and feline liver diseases has not been studied in detail, but the same mechanism of inhibition by drugs as in humans could play a role in veterinary medicine.

ABC transporters in the eyes of dogs and implications in drug therapy.

Purpose: The current study aims to quantifies the level of expression of selected adenosine triphosphate-binding cassette (ABC) efflux transporters and the major drug metabolizing enzyme CYP450 3A12 in the eyes of dogs.

Materials And Methods: The levels of expression were quantified by real-time polymerase chain reaction in the cornea, conjunctiva and retinal tissue.

Results: ABCB1 mRNA is present at high levels in all analysed tissues.

Drug metabolism of CYP3A4, CYP2C9 and CYP2D6 substrates in pigs and humans.

Pigs are becoming increasingly used as a test animal both in pharmacological and toxicological assessment of new drug compounds. For interspecies comparisons and predictions it is important to characterize the expression and function of membrane transport and enzymatic proteins in pigs, particularly at a mechanistic level which will make extrapolation of observation between pig and man to be made with more confidence. The major objective of this report was to increase the integrative knowledge of drug metabolism in pigs and to compare with corresponding data from human liver microsomes.