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In Vitro Drug-Drug Interaction Screens for Canine Veterinary Medicines: Evaluation of Cytochrome P450 Reversible Inhibition

Washington State University, School of Molecular Biosciences, Pullman, Washington (D.A.); and Pfizer Animal Health, Pfizer, Inc., Veterinary Medicine Research and Development, Metabolism and Safety, Kalamazoo, Michigan (M.J.Z., P.B.M., C.W.L.)

Little information regarding the metabolic pathways of pharmaceutical agents administered to dogs, or the inhibition of those metabolic pathways, is available. Without this information, it is difficult to assess how combinations of drugs, whether new or old or approved or nonapproved, may increase the risk for metabolic drug-drug interactions in dogs. Because mammalian xenobiotic metabolism pathways often involve the hepatic cytochrome P450 (P450) monooxgenases, canine liver microsome P450 inhibition screens were tested to evaluate the potential metabolic drug interaction risk of commonly used veterinary medicines. A probe substrate cocktail was developed for four of the five major hepatic canine P450s and used to evaluate their inhibition by 45 canine therapeutic agents in a single-point IC₅₀ screen. Moderate inhibitors (>25%) were further characterized with an automated ninepoint IC₅₀ assay that identified ketoconazole, clomipramine, and loperamide as submicromolar CYP2D15 inhibitors. Additional inhibitors belonged to the antiemetic, antimitotic, and anxiolytic therapeutic classes. According to the marker activities, the relative frequency of P450 inhibition by isoform followed the sequence CYP2D15 > CYP2B11 > CYP2C21/41 > CYP3A12/26 > CYP1A1/2. The findings presented suggest there is some overlap in canine and human P450 inhibition specificity. However, occasional differences may give human drugs used off-label in dogs unexpected P450 inhibition profiles and, therefore, cause an unexpected drug-drug interaction risk.