Comparison of predicted intrinsic hepatic clearance of 30 pharmaceuticals in canine and feline liver microsomes

Abstract

1. Known cytochrome P450 (CYP) substrates in humans are used in veterinary medicine, with limited knowledge of the similarity or variation in CYP metabolism. Comparison of canine and feline CYP metabolism via liver microsomes report that human CYP probes and inhibitors demonstrate differing rates of intrinsic clearance (CLint).2. The purpose of this study was to utilize a high-throughput liver microsome substrate depletion assay, combined with microsomal and plasma protein binding to compare the predicted hepatic clearance (CLhep) of thirty therapeutic agents used off-label in canines and felines, using both the well-stirred and parallel tube models.3. In canine liver microsomes, 3/30 substrates did not have quantifiable CLint, while midazolam and amitriptyline CLint was too rapid for accurate determination. A CLhep was calculated for 29/30 substrates in feline microsomes. Overall, canine CLhep was faster compared to the feline, with fold differences ranging from 2–20-fold.4. A comparison between the well-stirred and parallel tube model indicates that the parallel tube model reports a slighter higher CLhep in both species.5. The differences in CYP metabolism between canine and feline highlight the need for additional research into CYP expression and specificity.