title: Metabolism of [2-14C]p-hydroxyphenyl acetic acid in rat, monkey and human hepatocytes and in bile-duct cannulated rats.
abstract: We determined the metabolism of [2-(14)C]p-hydroxyphenyl acetic acid (p-HPA) in rat (male, Sprague-Dawley), monkey (male, Cynomolgus), and human (male, Caucasian) hepatocytes, and in bile-duct cannulated (BDC) rats (male, Sprague-Dawley). Unchanged p-HPA ranged from 87.0 to 92.6% of the total radioactivity (TRA) in the extracts of rat, monkey, and human hepatocytes. Metabolites M1 (a glucuronide conjugate of p-HPA) and M2 (a glycine conjugate of p-HPA) were detected, accounting for 1-4% of TRA. After an oral dose of [2-(14)C]p-HPA to BDC rats, p-HPA-related components was predominantly excreted in urine, accounting for 83% of the dose. Bile excretion was limited, accounting for only 1.5% of the dose. Unchanged p-HPA was the predominant radioactivity in plasma (84.6% of the TRA in 1-h pooled plasma) and urine (69.6% of the dose). Metabolites M1, M2, and M3 (a glucuronide of p-HPA) were all detected in plasma, urine, and bile as minor components. In summary, p-HPA was not metabolized extensively in rat, monkey, and human hepatocytes. In rats, absorption and elimination of p-HPA were nearly complete with urinary excretion of the unchanged p-HPA as the predominant route of elimination after oral dosing. No oxidative metabolites were detected, suggesting a minimal role for P450 enzymes in its overall metabolic clearance. Therefore, p-HPA has a low potential for drug-drug interactions mediated by the concomitant inhibitors and inducers of P450 enzymes.
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Co., Princeton, New Jersey 08543, USA. Lian.zhou@bms.com
authors.forename: Lian
authors.initials: L
authors.lastname: Zhou
authors.forename: Peggy
authors.initials: P
authors.lastname: Liu-Kreyche
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001711:Biotransformation; D002404:Catheterization; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008297:Male; D010648:Phenylacetates / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000975:Antioxidants; D010648:Phenylacetates; C008070:4-hydroxyphenylacetic acid