title: Comparative metabolism of radiolabeled muraglitazar in animals and humans by quantitative and qualitative metabolite profiling.
abstract: Muraglitazar (Pargluva), a dual alpha/gamma 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 [(14)C]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 [(14)C]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 PPARalpha/gamma 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.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543, USA. donglu.zhang@bms.com
authors.forename: Donglu
authors.initials: D
authors.lastname: Zhang
authors.forename: Lifei
authors.initials: L
authors.lastname: Wang
authors.forename: Nirmala
authors.initials: N
authors.lastname: Raghavan
authors.forename: Haiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Wenying
authors.initials: W
authors.lastname: Li
authors.forename: Peter T
authors.initials: PT
authors.lastname: Cheng
authors.forename: Ming
authors.initials: M
authors.lastname: Yao
authors.forename: Litao
authors.initials: L
authors.lastname: Zhang
authors.forename: Mingshe
authors.initials: M
authors.lastname: Zhu
authors.forename: Samuel
authors.initials: S
authors.lastname: Bonacorsi
authors.forename: Suresh
authors.initials: S
authors.lastname: Yeola
authors.forename: James
authors.initials: J
authors.lastname: Mitroka
authors.forename: Narayanan
authors.initials: N
authors.lastname: Hariharan
authors.forename: Vinayak
authors.initials: V
authors.lastname: Hosagrahara
authors.forename: Gamini
authors.initials: G
authors.lastname: Chandrasena
authors.forename: Wen Chyi
authors.initials: WC
authors.lastname: Shyu
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
mesh_terms: D000818:Animals; D001646:Bile / Q000737:chemistry; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005998:Glycine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D005998:Glycine; C500085:muraglitazar