Effects of gender, AIDS, and acetylator status on intrapulmonary concentrations of isoniazid
Effects of gender, AIDS, and acetylator status on intrapulmonary concentrations of isoniazid
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DOI：
10.1128/aac.46.8.2358-2364.2002
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发表时间：
2002-08-01
影响因子：
4.9
通讯作者：
Zurlinden, E
中科院分区：
文献类型：
--
作者：
Conte, JE;Golden, JA;Zurlinden, E
本研究的目的是评估性别、艾滋病和乙酰化状态对口服异烟肼血浆和肺稳态浓度的影响。80名成人志愿者接受异烟肼300 mg每日一次给药，持续5天。受试者根据性别、是否患有艾滋病和乙酰化状态被分配到8个区组。在首次给药前、末次给药后1 h以及末次给药后4 h完成支气管镜检查和支气管肺泡灌洗（BAL）时采集血液。咖啡因的代谢被用来确定乙酰化状态。在无全身镇静的情况下进行标准化支气管镜检查。用尿素稀释法计算上皮衬里液（ELF）的回收量。采用高效液相色谱法测定血浆、BAL液和肺泡细胞（AC）中的异烟肼浓度。艾滋病状态或性别对异烟肼在1或4 h的血浆浓度无显著影响。4小时血浆中的浓度和ELF中的浓度在慢乙酰化者中高于快乙酰化者。末次给药后1 h的血浆浓度（1.85+/-1.60 mug/ml [平均值+/-标准差; n=80]）与ELF（2.25+/-3.50 mug/ml）或AC（2.61+/-5.01 mug/ml）无显著差异。对于整个研究组，1小时时分别有34.7%、60%和82.7%的受试者血浆浓度低于1.0、2.0和3.0 μ g/ml; 30例ELF中的浓度低于1.0、2.0和3.0 μ g/ml，（37.5%）、53（66.0%），58（72.5%）; AC中的浓度分别在43（53.8%）、59（73.8%）和65（81.3%）例受试者中低于1.0、2.0和3.0 μ g/ml。口服异烟肼在血浆中的浓度不受性别或艾滋病的影响。在4小时的血浆中的浓度和ELF中的浓度，但不是在AC中的浓度，在缓慢乙酰化显著大于快速乙酰化。血浆和肺中的浓度低于推荐的血浆治疗浓度和已发表的异烟肼对结核分枝杆菌的MIC。异烟肼在AC和ELF中的最佳浓度尚不清楚，但这些数据表明药物通过被动扩散进入这些隔室，并达到与血浆中发现的浓度相似的浓度。
The objective of the present study was to evaluate the effects of gender, AIDS, and acetylator status on the steady-state concentrations of orally administered isoniazid in plasma and lungs. Isoniazid was administered at 300 mg once daily for 5 days to 80 adult volunteers. Subjects were assigned to eight blocks according to gender, presence or absence of AIDS, and acetylator status. Blood was obtained prior to administration of the first dose, 1 h after administration of the last dose, and at the completion of bronchoscopy and bronchoalveolar lavage (BAL), which was performed 4 h after administration of the last dose. The metabolism of caffeine was used to determine acetylator status. Standardized bronchoscopy was performed without systemic sedation. The volume of epithelial lining fluid (ELF) recovered was calculated by the urea dilution method. Isoniazid concentrations in plasma, BAL fluid, and alveolar cells (ACs) were measured by high-performance liquid chromatography. AIDS status or gender had no significant effect on the concentrations of isoniazid in plasma at 1 or 4 h. Concentrations in plasma at 4 h and concentrations in ELF were greater in slow acetylators than fast acetylators. The concentration in plasma (1.85+/-1.60 mug/ml [mean +/- standard deviation; n=80]) at 1 h following administration of the last dose was not significantly different from that in ELF (2.25+/-3.50 mug/ml) or ACs (2.61+/-5.01 mug/ml). For the entire study group, concentrations in plasma at 1 h were less than 1.0, 2.0, and 3.0 mug/ml for 34.7, 60, and 82.7% of the subjects, respectively; concentrations in ELF were less than 1.0, 2.0, and 3.0 mug/ml in 30 (37.5%), 53 (66.0%), and 58 (72.5%) of the subjects, respectively; and concentrations in ACs were less than 1.0, 2.0, and 3.0 mug/ml in 43 (53.8%), 59 (73.8%), and 65 (81.3%) of the subjects, respectively. The concentrations of orally administered isoniazid in plasma were not affected by gender or the presence of AIDS. The concentrations in plasma at 4 h and the concentrations in ELF, but not the concentrations in ACs, were significantly greater in slow acetylators than fast acetylators. Concentrations in plasma and lungs were low compared to recommended therapeutic concentrations in plasma and published MICs of isoniazid for Mycobacterium tuberculosis. The optimal concentrations of isoniazid in ACs and ELF are unknown, but these data suggest that the drug enters these compartments by passive diffusion and achieves concentrations similar to those found in plasma.