Protein Abundance of Hydrolytic Drug Metabolizing Enzymes in Different Tissues and across Species.

Hydrolytic drug-metabolizing enzymes (hydrolases) are essential for the metabolism of many therapeutic agents; however, comprehensive data on their tissue distribution and interspecies variability remain limited. To address this knowledge gap, the primary objective of this study was to quantify the abundance of drug metabolism-relevant hydrolases (e.g., CES1/2, PON1/2/3, BPHL, APEH, CMBL, EPHX1/2, DPP4, and AADAC) across liver, intestine, and kidney tissues in humans, rats, mice, dogs, and monkeys using a comprehensive global proteomics approach. Further, we present here qualitative and quantitative differences in intertissue and interspecies variability among 182 detected hydrolases. Humans exhibited the greatest variability of hydrolases across tissues, with marked qualitative and quantitative differences in protein abundance observed between species. Orthology analysis highlighted substantial sequence conservation in monkeys but greater divergence in rodents and dogs. Overall, these findings could provide critical quantitative data to inform animal model selection and improve the translation of preclinical drug metabolism studies to humans for drugs that are majorly metabolized by hydrolases.