Genetic polymorphisms of drug-metabolizing cytochromes P450 and flavin-containing monooxygenases in dogs and pigs inform the prediction of drug metabolism and toxicity in humans and other animal species.

Drug oxygenation is primarily carried out by cytochromes P450 (P450s, CYPs) and by flavin-containing monooxygenases (FMOs). Genetic variations of P450s and FMOs significantly contribute to differences in drug metabolism among individuals and populations. Moreover, species-specific differences in drug metabolism pose challenges during drug discovery and development. Dogs and pigs are commonly used as animal models in preclinical drug development studies. Consequently, this mini-review updates and summarizes the data from dogs and pigs used as models for predicting and comparing human drug metabolism. This research update presents the most recent findings on genetic variants of P450 and FMO enzymes in dogs and pigs and makes comparisons with their human counterparts. Recently, genetic variants of dog CYP2B6 and CYP2C21 have been identified and analyzed. In dog CYP2B6, the V103I, Q233L, and R145Q variants exhibited reduced propofol oxidation activities compared to the wild type, whereas a splice variant resulting in E275del demonstrated increased metabolic activity. In dog CYP2C21, the R125C variant showed diminished omeprazole oxidation activity relative to the wild type, and a frameshift variant (c.669dupA) led to a truncated protein, rendering it a null allele. Furthermore, liver microsomes from minipigs with CYP1A2 variant F260L showed reduced caffeine C8-hydroxylation activity compared to the wild type. Additional information on other P450s and FMOs is included. The summarized information enhances our understanding of individual pharmacokinetic and toxicological outcomes in dogs and pigs used as preclinical models and illuminates the molecular mechanisms of P450 and FMO functionality in humans.