Matsuki Y, Hongu Y, Noda Y, Kiwada H, Sakurai H, Goromaru T
Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
Yakugaku Zasshi. 1992 Dec;112(12):926-33. doi: 10.1248/yakushi1947.112.12_926.
The effects of ascorbic acid (AA) on the metabolic fate of iproniazid (IPN) and on the free radical intermediates derived from IPN were investigated in rats. After oral administration of IPN with or without AA, the plasma concentration and the urinary excretion of IPN and its metabolites were determined by gas chromatography-mass spectrometry using stable isotope labeled compounds as internal standards. In the excretion of IPN and its metabolites except hydrazine (Hy), the differences between co-administration and single administration were not observed. The excretion of Hy, which is a known hepatotoxic metabolite, decreased clearly in the co-administration of IPN and AA. When IPN and AA were co-administered orally, the profiles of plasma levels of IPN and its metabolites were almost similar after the administration of IPN alone. Furthermore, no differences between i.v. co-administration and i.v. administration alone were observed. These results indicated that AA did not affect both absorption and metabolism of IPN. By the electron spin resonance (ESR) spectroscopy and spin-trapping technique, the ESR signals due to the alpha-(4-pyridyl 1-oxide)-N-tert-butylnitrone (4-POBN) adducts induced by isopropylhydrazine (IP-Hy) were two-fold higher than those by IPN in microsomal systems. The free radical formations of IPN and IP-Hy were significantly inhibited by AA in a dose dependent manner. The 4-POBN-trapped radical species generated from IPN and IP-Hy were presumed to be an isopropyl radical by the results of mass spectrometry.(ABSTRACT TRUNCATED AT 250 WORDS)
在大鼠中研究了抗坏血酸（AA）对异烟肼（IPN）代谢命运及其衍生的自由基中间体的影响。口服给予IPN（伴或不伴AA）后，以稳定同位素标记化合物为内标，采用气相色谱 - 质谱法测定血浆中IPN及其代谢产物的浓度以及尿排泄量。在IPN及其除肼（Hy）之外的代谢产物的排泄方面，未观察到联合给药与单次给药之间的差异。已知具有肝毒性的代谢产物Hy的排泄量在IPN与AA联合给药时明显降低。当IPN和AA口服联合给药时，单独给予IPN后血浆中IPN及其代谢产物水平的变化曲线几乎相似。此外，静脉联合给药与单独静脉给药之间未观察到差异。这些结果表明AA不影响IPN的吸收和代谢。通过电子自旋共振（ESR）光谱和自旋捕集技术，在微粒体系统中，由异丙肼（IP - Hy）诱导的α-（4 - 吡啶基1 - 氧化物）-N - 叔丁基硝酮（4 - POBN）加合物产生的ESR信号比IPN产生的高两倍。AA以剂量依赖性方式显著抑制IPN和IP - Hy的自由基形成。根据质谱结果推测，由IPN和IP - Hy产生的被4 - POBN捕获的自由基种类为异丙基自由基。（摘要截断于250字）
