| Metabolism and Disposition of Eltrombopag, an Oral, Nonpeptide Thrombopoietin Receptor Agonist, in Healthy Human Subjects. | |
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MedLine Citation:
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PMID: 21646437 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The metabolism and disposition of eltrombopag, the first-in-class small molecule human thrombopoietin receptor agonist, were studied in six healthy men following a single oral administration of a solution dose of [(14)C]eltrombopag (75 mg, 100 μCi). Eltrombopag was well tolerated. The drug was quickly absorbed and was the predominant circulating component in plasma (accounting for 63% of the total plasma radioactivity). A mono-oxygenation metabolite (M1) and acyl glucuronides (M2) of eltrombopag were minor circulating components. The predominant route of elimination of radioactivity was fecal (58.9%). Feces contained about 20% of dose as glutathione related conjugates (M5, M6 and M7) and another 20% as unchanged eltrombopag. The glutathione conjugates were likely detoxification products of a p-imine methide intermediate formed by metabolism of M1, which arises through P450 dependent processes. Low levels of covalently bound drug-related intermediates to plasma proteins were detected, which could result from the reaction of the imine methide or acyl glucuronide conjugates with proteins. The bound material contributes to the longer plasma elimination half life of radioactivity. Renal elimination of conjugates of hydrazine cleavage metabolites (mostly as M3 and M4) accounted for 31% of the radio-dose, with no unchanged eltrombopag detected in urine. The urinary metabolites appear to be products of gut microbial cleavage. |
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Authors:
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Yanli Deng; Armina Madatian; Mary Beth Wire; Carolyn Bowen; Jungwook Park; Daphne Williams; Bin Peng; Ernest Schubert; Frances Gorycki; Mark Levy; Peter Gorycki |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-6-6 |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: - ISSN: 1521-009X ISO Abbreviation: - Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-6-7 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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1 GlaxoSmithKline Pharmaceuticals; |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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