| Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent. | |
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MedLine Citation:
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PMID: 14744939 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glucuronides of piperazine hydroxylamines are rarely reported in the literature, and even more rarely are their structures unambiguously identified. One major metabolite was detected by liquid chromatography/mass spectrometry-radioactivity in urine from monkeys treated with the aryl piperazine oral hypoglycemic agent 9-[(1S,2R)-2-fluoro-1-methylpropyl]-2-methoxy-6-(1-piperazinyl) purine hydrochloride (1). The mass spectrum of this metabolite indicated that it was both monooxygenated and glucuronidated on the piperazine ring. Possible structures included the N- or O-glucuronic acid conjugates of a carbinolamine, hydroxylamine, or N-oxide. Treatment with beta-glucuronidase gave a monooxygenated derivative of the parent compound. 1H NMR analysis of either the glucuronic acid conjugate or the monooxygenated product provided insufficient evidence to unambiguously determine their structures. Incubation of 1 with pig liver microsomes resulted in formation of the same monooxygenated derivative derived from beta-glucuronidase treatment of the glucuronide metabolite. This in vitro system was used to generate sufficient material for analysis by 13C NMR, and the metabolite was identified as a hydroxylamine derivative 2. Incubation of the hydroxylamine with monkey liver microsomes and uridine diphospho-5'-glucuronic acid gave the same glucuronic acid conjugate as that observed in monkey urine. 13C NMR analysis of this biosynthetic product led to its unequivocal structure assignment as the O-glucuronic acid conjugate of the hydroxylamine 3. |
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Authors:
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Randall R Miller; George A Doss; Ralph A Stearns |
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Publication Detail:
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Type: In Vitro; Journal Article |
Journal Detail:
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Title: Drug metabolism and disposition: the biological fate of chemicals Volume: 32 ISSN: 0090-9556 ISO Abbreviation: Drug Metab. Dispos. Publication Date: 2004 Feb |
Date Detail:
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Created Date: 2004-01-27 Completed Date: 2004-03-30 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9421550 Medline TA: Drug Metab Dispos Country: United States |
Other Details:
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Languages: eng Pagination: 178-85 Citation Subset: IM |
Affiliation:
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Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA. randy_miller@merck.com |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Animals Chromatography, High Pressure Liquid Chromatography, Liquid Glucuronides / biosynthesis, metabolism*, urine Hydroxylamines / metabolism*, urine Hypoglycemic Agents / administration & dosage, metabolism*, urine Macaca mulatta Magnetic Resonance Spectroscopy Male Mass Spectrometry Microsomes, Liver / enzymology Piperazines / administration & dosage, metabolism*, urine Species Specificity Swine |
| Chemical | |
Reg. No./Substance:
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0/Glucuronides; 0/Hydroxylamines; 0/Hypoglycemic Agents; 0/L 686398; 0/Piperazines |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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