Received for publication October 14, 2005.
Revised January 11, 2006.
Accepted for publication February 2, 2006.

BIOTRANSFORMATION OF CARBON-14 LABELED MURAGLITAZAR IN MALE MICE: INTERSPECIES DIFFERENCE IN METABOLIC PATHWAYS LEADING TO UNIQUE METABOLITES

Abstract

Muraglitazar (Pargluva^TM), a dual alpha/gamma PPAR (peroxisome proliferator-activated receptor) activator, is under development for treatment of type 2 diabetes. This study describes the biotransformation profile of carbon-14 labeled muraglitazar in plasma, urine, feces, and bile samples from male CD-1 mice (intact and BDC) following single oral doses of 1 and 40 mg/kg. The major drug-related component circulating in mouse plasma was the parent compound for up to 4 h post dose. Similar to excretion profiles of muraglitazar in humans, monkeys, and rats, urinary excretion was minor and fecal excretion via the biliary route was the major elimination pathway for muraglitazar in mice. The parent compound was a minor component in urine, bile and feces, indicating that muraglitazar was extensively metabolized in mice. Major biotransformation pathways of muraglitazar in mice included taurine conjugate formation, acyl glucuronidation, hydroxylation, and O-dealkylation. In addition to those metabolites previously identified in humans, monkeys, and rats (M1-M21), several unique metabolites identified in mice included taurine conjugates (M24, M25, M26a,b,c and M31), oxazole-ring opened metabolites (M27 and M28), glutathione conjugates (M29a,b and M30), a dihydroxylated metabolite (M32), hydroxylated metabolites (M33 and M35), and a dehydrogenated metabolite (M34). The taurine conjugate of muraglitazar, M24, was a major metabolite in mice, accounting for 12-15% of the total dose in BDC mice or 7-12% of the total dose in intact mice. None of these taurine and glutathione conjugates were found in the bile samples of humans, monkeys, or rats.

Key words: biliary excretion, drug clearance, drug discovery, drug disposition, excretion, HPLC, mass spectrometry, metabolite identification, phase II drug metabolism, structure elucidation

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