Pharmacokinetics and Metabolism of A Human 11β-HSD1 Inhibitor

摘要

Pharmacokinetics and metabolism of compound 15, a potent and selective inhibitor of human 11β-HSD1, was evaluated in preclinical species. Following i.v. administration, compound 15 exhibited low clearance cross species. After oral administration, compound 15 was absorbed reasonably well with bioavailability ranging from 24% in monkey to 88% in dog. About 23% of an i.v. dose of ~(14)C-labeled compound 15 was excreted in rat bile, feces, and urine as parent molecule over a period of 72 h, suggesting that biotransformation is the major route of elimination of compound 15 in rat. Using liquid chromatography-tandem mass spectrometry (LC/MS/MS), six metabolites of compound 15 were identified in rat in vivo. Four metabolites (M1, M2, M3, and M4) were detected in hepatocyte incubations. No unique human metabolite was observed in vitro. The metabolites formed by human hepatocytes were produced by rat and monkey, the species used in toxicological evaluation of compound 15. Animal and human hepatocyte intrinsic clearance of compound 15 values were scaled up to predict its in vivo hepatic clearance. Good in vivo in vitro correlation (within 2 fold error) was observed in preclinical species. Compound15 was predicted to exhibit low clearance in human.