RT Journal Article
SR Electronic
T1 Comparative Metabolism of Radiolabeled Muraglitazar in Animals and Humans by Quantitative and Qualitative Metabolite Profiling
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 150
OP 167
DO 10.1124/dmd.106.012450
VO 35
IS 1
A1 Donglu Zhang
A1 Lifei Wang
A1 Nirmala Raghavan
A1 Haiying Zhang
A1 Wenying Li
A1 Peter T. Cheng
A1 Ming Yao
A1 Litao Zhang
A1 Mingshe Zhu
A1 Samuel Bonacorsi
A1 Suresh Yeola
A1 James Mitroka
A1 Narayanan Hariharan
A1 Vinayak Hosagrahara
A1 Gamini Chandrasena
A1 Wen Chyi Shyu
A1 W. Griffith Humphreys
YR 2007
UL http://dmd.aspetjournals.org/content/35/1/150.abstract
AB Muraglitazar (Pargluva), a dual α/γ peroxisome proliferator-activated receptor (PPAR) activator, has both glucose- and lipid-lowering effects in animal models and in patients with diabetes. This study describes the in vivo and in vitro comparative metabolism of [14C]muraglitazar in rats, dogs, monkeys, and humans by quantitative and qualitative metabolite profiling. Metabolite identification and quantification methods used in these studies included liquid chromatography/mass spectrometry (LC/MS), LC/tandem MS, LC/radiodetection, LC/UV, and a newly described mass defect filtering technique in conjunction with high resolution MS. After oral administration of [14C]muraglitazar, absorption was rapid in all species, reaching a concentration peak for parent and total radioactivity in plasma within 1 h. The most abundant component in plasma at all times in all species was the parent drug, and no metabolite was present in greater than 2.5% of the muraglitazar concentrations at 1 h postdose in rats, dogs, and humans. All metabolites observed in human plasma were also present in rats, dogs, or monkeys. Urinary excretion of radioactivity was low (<5% of the dose) in all intact species, and the primary route of elimination was via biliary excretion in rats, monkeys, and humans. Based on recovered doses in urine and bile, muraglitazar showed a very good absorption in rats, monkeys, and humans. The major drug-related components in bile of rats, monkeys, and humans were glucuronides of muraglitazar and its oxidative metabolites. The parent compound was a minor component in bile, suggesting extensive metabolism of the drug. In contrast, the parent drug and oxidative metabolites were the major components in feces, and no glucuronide conjugates were found, suggesting that glucuronide metabolites were excreted in bile and hydrolyzed in the gastrointestinal tract. The metabolites of muraglitazar resulted from both glucuronidation and oxidation. The metabolites in general had greatly reduced activity as PPARα/γ activators relative to muraglitazar. In conclusion, muraglitazar was rapidly absorbed, extensively metabolized through glucuronidation and oxidation, and mainly eliminated in the feces via biliary excretion of glucuronide metabolites in all species studied. Disposition and metabolic pathways were qualitatively similar in rats, dogs, monkeys, and humans. The American Society for Pharmacology and Experimental Therapeutics