Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent.
Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent.
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口服降血糖药羟胺葡萄糖醛酸代谢物的鉴定。
DOI：
10.1124/dmd.32.2.178
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
R. Stearns
中科院分区：
文献类型：
--
作者：
Randall R. Miller;G. Doss;R. Stearns
哌嗪羟胺的葡萄糖醛酸苷在文献中很少报道，甚至更少的是它们的结构明确确定。通过液相色谱/质谱法-放射性，在接受芳基哌嗪口服降糖药9-[（1 S，2 R）-2-氟-1-甲基丙基]-2-甲氧基-6-（1-哌嗪基）嘌呤盐酸盐（1）给药的猴尿液中检测到一种主要代谢产物。该代谢产物的质谱表明，其在哌嗪环上既被单氧化又被葡萄糖醛酸化。可能的结构包括甲醇胺、羟胺或N-氧化物的N-或O-葡萄糖醛酸共轭物。用β-葡萄糖醛酸酶处理得到母体化合物的单氧衍生物。葡萄糖醛酸结合物或单氧化产物的1H NMR分析提供的证据不足以明确确定其结构。将1与猪肝微粒体孵育，导致形成相同的单氧衍生物，该衍生物源自β-葡萄糖醛酸酶处理葡萄糖醛酸代谢物。该体外系统用于产生足够的材料以通过13 C NMR进行分析，并且代谢物被鉴定为羟胺衍生物2。将羟胺与猴肝微粒体和尿苷二磷酸-5 '-葡萄糖醛酸孵育，得到与猴尿液中观察到的相同的葡萄糖醛酸结合物。该生物合成产物的13 C NMR分析导致其明确的结构归属为羟胺3的O-葡萄糖醛酸缀合物。
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.