PT - JOURNAL ARTICLE AU - Lifei Wang AU - Donglu Zhang AU - Arun Swaminathan AU - Yongjun Xue AU - Peter T. Cheng AU - Shung Wu AU - Rogelio Mosqueda-Garcia AU - Catherine Aurang AU - Donald W. Everett AU - W. Griffith Humphreys TI - GLUCURONIDATION AS A MAJOR METABOLIC CLEARANCE PATHWAY OF <sup>14</sup>C-LABELED MURAGLITAZAR IN HUMANS: METABOLIC PROFILES IN SUBJECTS WITH OR WITHOUT BILE COLLECTION AID - 10.1124/dmd.105.007617 DP - 2006 Mar 01 TA - Drug Metabolism and Disposition PG - 427--439 VI - 34 IP - 3 4099 - http://dmd.aspetjournals.org/content/34/3/427.short 4100 - http://dmd.aspetjournals.org/content/34/3/427.full SO - Drug Metab Dispos2006 Mar 01; 34 AB - The metabolism and disposition of 14C-labeled muraglitazar (Pargluva), a novel dual α/γ peroxisome proliferator-activated receptor activator, was investigated in eight healthy male subjects with and without bile collection (groups 1 and 2) after a single 20-mg oral dose. Bile samples were collected for 3 to 8 h after dosing from group 2 subjects in addition to the urine and feces collection. In plasma, the parent compound was the major component, and circulating metabolites, including several glucuronide conjugates, were minor components at all time points. The exposure to parent drug (Cmax and area under the plasma concentration versus time curve) in subjects with bile collection was generally lower than that in subjects without bile collection. The major portion of the radioactive dose was recovered in feces (91% for group 1 and 51% for group 2). In addition, 40% of the dose was recovered in the bile from group 2 subjects. In this 3- to 8-h bile, the glucuronide of muraglitazar (M13, 15% of dose) and the glucuronides of its oxidative metabolites (M17a,b,c, M18a,b,c, and M20, together, 16% of dose) accounted for approximately 80% of the biliary radioactivity; muraglitazar and its O-demethylated metabolite (M15) each accounted for approximately 4% of the dose. In contrast, fecal samples only contained muraglitazar and its oxidative metabolites, suggesting hydrolysis of biliary glucuronides in the intestine before fecal excretion. Thus, the subjects with and without bile collection showed different metabolic profiles of muraglitazar after oral administration, and glucuronidation was not observed as a major pathway of metabolic clearance from subjects with the conventional urine and fecal collection, but was found as a major elimination pathway from subjects with bile collection. The American Society for Pharmacology and Experimental Therapeutics