RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 427
OP 439
DO 10.1124/dmd.105.007617
VO 34
IS 3
A1 Lifei Wang
A1 Donglu Zhang
A1 Arun Swaminathan
A1 Yongjun Xue
A1 Peter T. Cheng
A1 Shung Wu
A1 Rogelio Mosqueda-Garcia
A1 Catherine Aurang
A1 Donald W. Everett
A1 W. Griffith Humphreys
YR 2006
UL http://dmd.aspetjournals.org/content/34/3/427.abstract
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