Received for publication September 29, 2005.
Revised December 13, 2005.
Accepted for publication December 19, 2005.

Glucuronidation as a major metabolic clearance pathway of C-14 labeled muraglitazar (Pargluva) in humans: Metabolic profiles in subjects with or without bile collection

Abstract

The metabolism and disposition of C-14 labeled muraglitazar (Pargluva), a novel dual alpha/gamma PPAR activator, was investigated in 8 healthy male subjects with and without bile collection (Groups 1 and 2) after a single 20 mg oral dose. Bile samples were collected for 3-8 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 (C_max and AUC) in subjects with bile collection was generally lower than 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 3-8 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 following 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.

Key words: biliary excretion, enterohepatic circulation, excretion, glucuronidation, HPLC, metabolite identification, pharmacokinetics

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