title: Glucuronidation as a major metabolic clearance pathway of 14c-labeled muraglitazar in humans: metabolic profiles in subjects with or without bile collection.
abstract: The metabolism and disposition of 14C-labeled muraglitazar (Pargluva), a novel dual alpha/gamma 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.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
authors.forename: Lifei
authors.initials: L
authors.lastname: Wang
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.forename: Arun
authors.initials: A
authors.lastname: Swaminathan
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Xue
authors.forename: Peter T
authors.initials: PT
authors.lastname: Cheng
authors.forename: Shung
authors.initials: S
authors.lastname: Wu
authors.forename: Rogelio
authors.initials: R
authors.lastname: Mosqueda-Garcia
authors.forename: Catherine
authors.initials: C
authors.lastname: Aurang
authors.forename: Donald W
authors.initials: DW
authors.lastname: Everett
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
mesh_terms: D001646:Bile / Q000737:chemistry*; D002250:Carbon Radioisotopes; D020719:Glucuronides / Q000378:metabolism*; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D050217:Metabolic Detoxication, Phase II; D015394:Molecular Structure; D010080:Oxazoles / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine; D047493:PPAR alpha / Q000819:agonists; D047495:PPAR gamma / Q000819:agonists
chemical_list: D002250:Carbon Radioisotopes; D020719:Glucuronides; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D005998:Glycine; C500085:muraglitazar