RT Journal Article
SR Electronic
T1 Pharmacokinetics and Metabolism in Rats, Dogs, and Monkeys of the Cathepsin K Inhibitor Odanacatib: Demethylation of a Methylsulfonyl Moiety as a Major Metabolic Pathway
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1079
OP 1087
DO 10.1124/dmd.110.037184
VO 39
IS 6
A1 Kelem Kassahun
A1 W. Cameron Black
A1 Deborah Nicoll-Griffith
A1 Ian McIntosh
A1 Nathalie Chauret
A1 Stephen Day
A1 Elizabeth Rosenberg
A1 Kenneth Koeplinger
YR 2011
UL http://dmd.aspetjournals.org/content/39/6/1079.abstract
AB Odanacatib is a potent cathespin K inhibitor that is being developed as a novel therapy for osteoporosis. The disposition and metabolism of odanacatib were evaluated in rats, dogs, and rhesus monkeys after intravenous and oral administration of [14C]odanacatib. Odanacatib was characterized by low systemic clearance in all species and by a long plasma half-life in monkeys (18 h) and dogs (64 h). The oral bioavailability was dependent on the vehicle used and ranged from 18% (monkey) to ∼100% (dog) at doses of 1 to 5 mg/kg, using nonaqueous vehicles. After intravenous and oral administration to intact rats and monkeys >90% of the dose was recovered, mainly in the feces. Studies in bile duct-cannulated animals indicated that biliary secretion was the major mode of elimination of radioactivity; odanacatib also underwent some intestinal secretion. In monkeys, odanacatib was almost completely eliminated by metabolism; metabolism also played a major role in the clearance of odanacatib in rats and dogs. The major metabolic pathways were methyl hydroxylation (formation of M8 and its derivatives), methyl sulfone demethylation (formation of M4 and its derivative M5), and glutathione conjugation (formation of the cyclized cysteinylglycine adduct M6 after addition of glutathione to the nitrile group of odanacatib). The major metabolites in rats [M4 (parent-14 Da) and M5 (oxygenated derivative of M4)] were determined to arise from a novel pathway that involved oxidative demethylation of the methylsulfonyl moiety of odanacatib. Overall, odanacatib displayed species-dependent metabolism, which explains, at least in part, the divergent plasma half-life observed.