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Research ArticleArticle

Comparative Metabolism of Radiolabeled Muraglitazar in Animals and Humans by Quantitative and Qualitative Metabolite Profiling

Donglu Zhang, Lifei Wang, Nirmala Raghavan, Haiying Zhang, Wenying Li, Peter T. Cheng, Ming Yao, Litao Zhang, Mingshe Zhu, Samuel Bonacorsi, Suresh Yeola, James Mitroka, Narayanan Hariharan, Vinayak Hosagrahara, Gamini Chandrasena, Wen Chyi Shyu and W. Griffith Humphreys
Drug Metabolism and Disposition January 2007, 35 (1) 150-167; DOI: https://doi.org/10.1124/dmd.106.012450
Donglu Zhang
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Lifei Wang
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Nirmala Raghavan
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Haiying Zhang
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Wenying Li
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Peter T. Cheng
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Ming Yao
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Litao Zhang
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Mingshe Zhu
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Samuel Bonacorsi
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Suresh Yeola
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James Mitroka
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Narayanan Hariharan
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Vinayak Hosagrahara
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Gamini Chandrasena
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Wen Chyi Shyu
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Abstract

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.

Footnotes

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.012450.

  • ABBREVIATIONS: PPAR, peroxisome proliferator-activated receptor; BDC, bile duct-cannulated; HPLC, high-performance liquid chromatography; IS, internal standard; AUC, concentration versus time curve; LC/MS/MS, liquid chromatography/tandem mass spectrometry; LC/MS, liquid chromatography/mass spectrometry.

    • Received August 11, 2006.
    • Accepted October 20, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (1)
Drug Metabolism and Disposition
Vol. 35, Issue 1
1 Jan 2007
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Research ArticleArticle

Comparative Metabolism of Radiolabeled Muraglitazar in Animals and Humans by Quantitative and Qualitative Metabolite Profiling

Donglu Zhang, Lifei Wang, Nirmala Raghavan, Haiying Zhang, Wenying Li, Peter T. Cheng, Ming Yao, Litao Zhang, Mingshe Zhu, Samuel Bonacorsi, Suresh Yeola, James Mitroka, Narayanan Hariharan, Vinayak Hosagrahara, Gamini Chandrasena, Wen Chyi Shyu and W. Griffith Humphreys
Drug Metabolism and Disposition January 1, 2007, 35 (1) 150-167; DOI: https://doi.org/10.1124/dmd.106.012450

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Research ArticleArticle

Comparative Metabolism of Radiolabeled Muraglitazar in Animals and Humans by Quantitative and Qualitative Metabolite Profiling

Donglu Zhang, Lifei Wang, Nirmala Raghavan, Haiying Zhang, Wenying Li, Peter T. Cheng, Ming Yao, Litao Zhang, Mingshe Zhu, Samuel Bonacorsi, Suresh Yeola, James Mitroka, Narayanan Hariharan, Vinayak Hosagrahara, Gamini Chandrasena, Wen Chyi Shyu and W. Griffith Humphreys
Drug Metabolism and Disposition January 1, 2007, 35 (1) 150-167; DOI: https://doi.org/10.1124/dmd.106.012450
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