Abstract

The metabolism and disposition of dual ¹⁴C-labeled peliglitazar, a dual α/γ peroxisome proliferator-activated receptor activator, was investigated in 10 healthy male subjects with and without bile collection (groups 1 and 2) after a single 10-mg oral dose. Serial blood samples, urine, and feces (0–240 h) as well as bile samples (3–8 h after dosing from group 2 subjects) were collected. The maximum plasma concentration (C_max) of drug was reached at approximately 1 h and the elimination half-life (t_1/2) was approximately 3.5 h. The exposure to drug metabolites (C_max and area under the plasma concentration versus time curve) was not significantly different between the two groups. The parent compound and its 1-O-β-acyl-glucuronide conjugate were the major components in plasma; other circulating metabolites, including several other glucuronide conjugates, were minor components at all time points. The major portion of the radioactive dose was recovered in feces (94% for group 1 and 32% for group 2). Approximately 24% of the radioactive dose was recovered in the bile from group 2 subjects, nearly all of which was assigned as glucuronides of peliglitazar and its oxidative metabolites (M14, M14a, M14b, M15, M15a, M15b, and M17). In contrast, fecal samples contained peliglitazar and its oxidative metabolites resulting from aliphatic/aryl hydroxylation, and O-demethylation. These results suggested that the major clearance pathway of peliglitazar was through biliary elimination of glucuronide conjugates, which were hydrolyzed to peliglitazar and its oxidative metabolites in the intestines before excretion.