Abstract
We determined the metabolism of [2-14C]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 [2-14C]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.
Acknowledgements
We thank Dr. Hongjian Zhang (PharmaResources, Shanghai, China) for helpful discussions.
Declaration of interest
All of the studies reported herein were supported by Bristol-Myers Squibb Co. All of the authors are employees of Bristol-Myers Squibb Co.