Lauterburg B H, Smith C V, Todd E L, Mitchell J R
J Pharmacol Exp Ther. 1985 Dec;235(3):566-70.
The plasma concentrations of isoniazid and its hydrazino metabolites, acetylisoniazid, acetylhydrazine and diacetylhydrazine, were measured by gas chromatography-mass spectrometry in 12 healthy subjects after the ingestion of 300 mg of isoniazid. The area under the plasma concentration-time curve of acetylisoniazid and diacetylhydrazine increased with increasing rate of acetylation of isoniazid. In contrast, the area under the plasma concentration-time curve of acetylhydrazine, the postulated precursor of a toxic metabolite formed from isoniazid, was greater in slow acetylators. This occurred even though rapid acetylators generated more acetylisoniazid and thus more acetylhydrazine from isoniazid, because the rapid acetylators also acetylated acetylhydrazine faster to diacetylhydrazine than did the slow acetylators. Due to this complex relationship between area under the plasma concentration-time curve of acetylhydrazine and the rate of isoniazid acetylation (i.e., a faster rate of formation of acetylhydrazine is accompanied by a faster clearance to diacetylhydrazine), the rate of acetylation of isoniazid minimally influences the exposure of most patients to acetylhydrazine. This pharmacokinetic analysis, however, also shows that the apparent plasma half-life of acetylhydrazine is about five times longer than the plasma half-life of isoniazid, and thus repeated doses of isoniazid should lead to an accumulation of acetylhydrazine in the slowest acetylators in which the plasma half-life of acetylhydrazine is 20-plus hr.(ABSTRACT TRUNCATED AT 250 WORDS)
在12名健康受试者口服300毫克异烟肼后，采用气相色谱 - 质谱法测定了异烟肼及其肼基代谢产物乙酰异烟肼、乙酰肼和二乙酰肼的血浆浓度。乙酰异烟肼和二乙酰肼的血浆浓度 - 时间曲线下面积随异烟肼乙酰化速率的增加而增加。相比之下，异烟肼形成的有毒代谢产物的假定前体乙酰肼的血浆浓度 - 时间曲线下面积在慢乙酰化者中更大。尽管快乙酰化者从异烟肼生成更多的乙酰异烟肼，从而生成更多的乙酰肼，但这种情况仍然发生，因为快乙酰化者将乙酰肼乙酰化为二乙酰肼的速度也比慢乙酰化者更快。由于乙酰肼的血浆浓度 - 时间曲线下面积与异烟肼乙酰化速率之间存在这种复杂关系（即乙酰肼形成速度越快，其清除为二乙酰肼的速度也越快），异烟肼的乙酰化速率对大多数患者乙酰肼的暴露影响最小。然而，该药代动力学分析还表明，乙酰肼的表观血浆半衰期约为异烟肼血浆半衰期的五倍，因此重复给予异烟肼会导致乙酰肼在最慢乙酰化者体内蓄积，其中乙酰肼的血浆半衰期超过20小时。（摘要截短于250字）
