Document Detail

Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent.
MedLine Citation:
PMID:  14744939     Owner:  NLM     Status:  MEDLINE    
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.
Randall R Miller; George A Doss; Ralph A Stearns
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Publication Detail:
Type:  In Vitro; Journal Article    
Journal Detail:
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:
Created Date:  2004-01-27     Completed Date:  2004-03-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  178-85     Citation Subset:  IM    
Department of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA.
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MeSH Terms
Administration, Oral
Chromatography, High Pressure Liquid
Chromatography, Liquid
Glucuronides / biosynthesis,  metabolism*,  urine
Hydroxylamines / metabolism*,  urine
Hypoglycemic Agents / administration & dosage,  metabolism*,  urine
Macaca mulatta
Magnetic Resonance Spectroscopy
Mass Spectrometry
Microsomes, Liver / enzymology
Piperazines / administration & dosage,  metabolism*,  urine
Species Specificity
Reg. No./Substance:
0/Glucuronides; 0/Hydroxylamines; 0/Hypoglycemic Agents; 0/L 686398; 0/Piperazines

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