RT Journal Article
SR Electronic
T1 IDENTIFICATION OF A HYDROXYLAMINE GLUCURONIDE METABOLITE OF AN ORAL HYPOGLYCEMIC AGENT
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 178
OP 185
DO 10.1124/dmd.32.2.178
VO 32
IS 2
A1 Randall R. Miller
A1 George A. Doss
A1 Ralph A. Stearns
YR 2004
UL http://dmd.aspetjournals.org/content/32/2/178.abstract
AB 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 β-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 β-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. The American Society for Pharmacology and Experimental Therapeutics