Comparison of Tissue Abundance of Non-Cytochrome P450 Drug-Metabolizing Enzymes by Quantitative Proteomics between Humans and Laboratory Animal Species.

Abstract

The use of animal pharmacokinetic models as surrogates for humans relies on the assumption that the drug disposition mechanisms are similar between preclinical species and humans. However, significant cross-species differences exist in the tissue distribution and protein abundance of drug-metabolizing enzymes (DMEs) and transporters. We quantified non-cytochrome P450 (non-CYP) DMEs across commonly used preclinical species (cynomolgus and rhesus monkeys, beagle dog, Sprague Dawley and Wistar Han rats, and CD1 mouse) and compared these data with previously obtained human data. Aldehyde oxidase was abundant in humans and monkeys while poorly expressed in rodents, and not expressed in dogs. Carboxylesterase (CES) 1 abundance was highest in the liver while CES2 was primarily expressed in the intestine in all species with notable species differences. For example, hepatic CES1 was 3× higher in humans than in monkeys, but hepatic CES2 was 3-5× higher in monkeys than in humans. Hepatic UDP-glucuronosyltransferase (UGT) 1A2 abundance was ∼4× higher in dogs compared with rats, whereas UGT1A3 abundance was 3-5× higher in dog livers than its ortholog in human and monkey livers. UGT1A6 abundance was 5-6× higher in human livers compared with monkey and dog livers. Hepatic sulfotransferase 1B1 abundance was 5-7× higher in rats compared with the rest of the species. These quantitative non-CYP proteomics data can be used to explain unique toxicological profiles across species and can be integrated into physiologically based pharmacokinetic models for the mechanistic explanation of pharmacokinetics and tissue distribution of xenobiotics in animal species. SIGNIFICANCE STATEMENT: We characterized the quantitative differences in non-cytochrome P450 (non-CYP) drug-metabolizing enzymes across commonly used preclinical species (cynomolgus and rhesus monkeys, beagle dogs, Sprague Dawley and Wistar Han rats, and CD1 mice) and compared these data with previously obtained human data. Unique differences in non-CYP enzymes across species were observed, which can be used to explain significant pharmacokinetic and toxicokinetic differences between experimental animals and humans.