| Case report of extensive metabolism by aldehyde oxidase in humans: Pharmacokinetics and metabolite profile of FK3453 in rats, dogs, and humans. | |
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MedLine Citation:
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PMID: 21385103 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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We describe the preclinical and clinical pharmacokinetic profiles of FK3453 [6-(2-amino-4-phenylpyrimidin-5-yl)-2-isopropylpyridazin-3(2H)-one] and the mechanism responsible for poor oral exposure of FK3453 in humans. FK3453 showed favourable profiles in preclinical pharmacokinetic studies, including satisfactory absolute bioavailability and total body clearance in animals (30.5%-41.4%, 54.7%-68.2%, and 71.3%-93.4% and 10.8-17.6, 1.9-17.1, and 5.0 mL/min/kg in male rats, female rats, and dogs, respectively), and good metabolic stability in liver microsomes (42.3, 14.5, and 1.1 mL/min/kg in male rats, dogs, and humans, respectively). However, despite these promising preclinical findings, plasma concentrations of FK3453 in humans were extremely low, with the oxidative metabolite of the aminopyrimidine moiety (M4) identified as a major metabolite. Given that aldehyde oxidase (AO) and xanthine oxidase (XO) were presumed to be the enzymes responsible for M4 formation, we investigated the mechanism of M4 formation using human liver subcellular fractions. M4 was detected in the incubation mixture with S9 and cytosol but not with microsomes, and M4 formation was inhibited by AO inhibitors (menadione, isovanillin) but not by cytochrome P-450 inhibitor (1-aminobenzotiazole) or XO inhibitor (allopurinol). These results suggest M4 formation is catalyzed by AO, and therefore, its poor exposure in humans was attributed to extensive AO metabolism. |
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Authors:
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Takafumi Akabane; Kohichiro Tanaka; Megumi Irie; Shigeyuki Terashita; Toshio Teramura |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-9 |
Journal Detail:
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Title: Xenobiotica; the fate of foreign compounds in biological systems Volume: - ISSN: 1366-5928 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 1306665 Medline TA: Xenobiotica Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Analysis & Pharmacokinetics Research Labs, Discovery Drug Metabolism & Pharmacokinetics, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba City, Ibaraki, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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