PT - JOURNAL ARTICLE AU - Abdul Basit AU - Peter W. Fan AU - S. Cyrus Khojasteh AU - Bernard P. Murray AU - Bill J. Smith AU - Scott Heyward AU - Bhagwat Prasad TI - <strong>Comparison of tissue abundance of non-cytochrome P450 drug metabolizing enzymes by quantitative proteomics between humans and laboratory animal species</strong> AID - 10.1124/dmd.121.000774 DP - 2021 Jan 01 TA - Drug Metabolism and Disposition PG - DMD-AR-2021-000774 4099 - http://dmd.aspetjournals.org/content/early/2021/12/30/dmd.121.000774.short 4100 - http://dmd.aspetjournals.org/content/early/2021/12/30/dmd.121.000774.full AB - 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 (AOX) was abundant in humans and monkeys while poorly expressed in rodents, and not expressed in dogs. Carboxylesterase 1 (CES1) 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-fold higher in humans than in monkeys, but hepatic CES2 was 3-5-fold higher in monkeys than in humans. Hepatic glucuronosyltransferase 1A2 (UGT1A2) abundance was ~4 fold higher in dog compared to rat, whereas UGT1A3 abundance was 3-5-fold higher in the dog liver than its orthologue in the human and monkey liver. UGT1A6 abundance was 5-6-fold higher in human liver compared to monkey and dog liver. Hepatic sulfotransferase 1B1 (SULT1B1) abundance was 5-7-fold higher in rats compared to 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 (PBPK) 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 dog, Sprague Dawley and Wistar Han rats, and CD1 mouse) 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.