Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis.
Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis.
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DOI：
10.1164/art.1954.70.2.266
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发表时间：
1954-08
期刊：
影响因子：
--
通讯作者：
Hughes Hb;Biehl Jp;Jones Ap;Schmidt Lh
中科院分区：
文献类型：
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作者：
Hughes Hb;Biehl Jp;Jones Ap;Schmidt Lh
本报告讨论了异烟肼在一组使用相对大剂量异烟肼治疗的块瘤患者中的代谢命运。这项调查源于两项独立的研究；第一个是关于异烟肼在人和猴子体内的代谢，第二个是关于肺结核病人对比常用剂量大一些的化合物的反应。这些研究中的第一个(1)明确地表明，n1 -异烟碱- n2 -乙酰肼是异烟肼在恒河猴体内的主要代谢产物，并表明这种乙酰衍生物也是在人体内的主要降解产物。第二项研究（2,3）表明，60%的患者耐受异硝唑，每日剂量为每公斤20毫克，持续16周或更长时间，无不良反应；其余40%的患者在接受了3至8周的治疗后，几乎所有患者都患上了周围神经炎。由于对低等动物的研究（4,5）表明，乙酰异烟肼的毒性仅为母体药物的一小部分，并且由于与磺胺类药物等其他治疗药物的研究（6,7）表明，人类对药物乙酰化的能力存在很大差异，因此提出了一个问题，即对异烟肼耐受性的差异是否取决于患者降解母体化合物的能力不同。幸运的是，来自原始患者组的材料可用于研究这个问题。由于与另一项调查(3)相关的原因，从这些患者中收集了相当一部分24小时尿液标本，并将等分液保存在4℃下，研究了这些标本中异烟肼、乙酰异烟肼和其他代谢产物的含量，结果如下所述。
This report deals with the metabolic fate of isoniazid in a group of tuber culous patients treated with relatively large doses of this drug. The investigation developed from two independent studies; the first on the metabolism of isoniazid in man and monkey, the second on the reactions of the tuberculous patient to doses of the compound somewhat larger than those commonly used. The first of these studies (1) showed unequivocally that N1-isonicotinyl-N2-acetylhydrazide is the major metabolic product of isoniazid in the rhesus monkey and sug gested that this acetyl derivative is also the major degradation product in man. The second (2, 3) showed that 60 per cent of the patients tolerated iso niazid in daily doses of 20 mg. per kg. for sixteen or more weeks without untoward reaction; the remaining 40 per cent developed peripheral neuritis, in nearly all cases after three to eight weeks of treatment. Since studies on lower animals (4, 5) had demonstrated that acetyl isoniazid possesses only a small fraction of the toxicity of the parent drug and since work with other therapeutic agents, such as the sulfonamides (6, 7), had shown that humans differ considerably in their capacities to acetylate drugs, the question was raised whether variations in tolerance to isoniazid rest on different capacities of patients to degrade the parent compound. Fortunately, material from the original group of patients was available for study of this question. For reasons pertinent to another investigation (3), twenty-four-hour urine specimens had been collected from a substantial fraction of these patients and aliquots had been stored at 4 C. These specimens were studied for content of isoniazid, acetyl isoniazid, and other metabolic products, with the results described below.