Conte John E, Golden Jeffrey A, Kipps Juliana, McIver Marina, Zurlinden Elisabeth
University of California, San Francisco, 350 Parnassus Ave., Suite 507, San Francisco, CA 94117, USA.
Antimicrob Agents Chemother. 2004 Oct;48(10):3823-7. doi: 10.1128/AAC.48.10.3823-3827.2004.
We determined the steady-state intrapulmonary pharmacokinetic and pharmacodynamic parameters of orally administered itraconazole (ITRA), 200 mg every 12 h (twice a day [b.i.d.]), on an empty stomach, for a total of 10 doses, in 26 healthy volunteers. Five subgroups each underwent standardized bronchoscopy and bronchoalveolar lavage (BAL) at 4, 8, 12, 16, and 24 h after administration of the last dose. ITRA and its main metabolite, 14-hydroxyitraconazole (OH-IT), were measured in plasma, BAL fluid, and alveolar cells (AC) using high-pressure liquid chromatography. Half-life and area under the concentration-time curves (AUC) in plasma, epithelial lining fluid (ELF), and AC were derived using noncompartmental analysis. ITRA and OH-IT maximum concentrations of drug (C(max)) (mean +/- standard deviation) in plasma, ELF, and AC were 2.1 +/- 0.8 and 3.3 +/- 1.0, 0.5 +/- 0.7 and 1.0 +/- 0.9, and 5.5 +/- 2.9 and 6.6 +/- 3.1 microg/ml, respectively. The ITRA and OH-IT AUC for plasma, ELF, and AC were 34.4 and 60.2, 7.4 and 18.9, and 101 and 134 microg. hr/ml. The ratio of the C(max) and the MIC at which 90% of the isolates were inhibited (MIC(90)), the AUC/MIC(90) ratio, and the percent dosing interval above MIC(90) for ITRA and OH-IT concentrations in AC were 1.1 and 3.2, 51 and 67, and 100 and 100%, respectively. Plasma, ELF, and AC concentrations of ITRA and OH-IT declined monoexponentially with half-lives of 23.1 and 37.2, 33.2 and 48.3, and 15.7 and 45.6 h, respectively. An oral dosing regimen of ITRA at 200 mg b.i.d. results in concentrations of ITRA and OH-ITRA in AC that are significantly greater than those in plasma or ELF and intrapulmonary pharmacodynamics that are favorable for the treatment of fungal respiratory infection.
我们在26名健康志愿者中确定了空腹口服伊曲康唑（ITRA）（每12小时200mg，一日两次）共10剂后的稳态肺内药代动力学和药效学参数。五个亚组在最后一剂给药后4、8、12、16和24小时分别接受标准化支气管镜检查和支气管肺泡灌洗（BAL）。使用高压液相色谱法测定血浆、BAL液和肺泡细胞（AC）中的ITRA及其主要代谢物14-羟基伊曲康唑（OH-IT）。采用非房室分析得出血浆、上皮衬液（ELF）和AC中的半衰期和浓度-时间曲线下面积（AUC）。血浆、ELF和AC中ITRA和OH-IT的最大药物浓度（C(max)）（平均值±标准差）分别为2.1±0.8和3.3±1.0、0.5±0.7和1.0±0.9、5.5±2.9和6.6±3.1μg/ml。血浆、ELF和AC中ITRA和OH-IT的AUC分别为34.4和60.2、7.4和18.9、101和134μg·hr/ml。AC中ITRA和OH-IT的C(max)与90%分离株被抑制时的最低抑菌浓度（MIC(90)）之比、AUC/MIC(90)比值以及高于MIC(90)的给药间隔百分比分别为1.1和3.2、51和67、100和100%。血浆、ELF和AC中ITRA和OH-IT的浓度呈单指数下降，半衰期分别为23.1和37.2、33.2和48.3、15.7和45.6小时。一日两次200mg的ITRA口服给药方案导致AC中ITRA和OH-ITRA的浓度显著高于血浆或ELF中的浓度，且肺内药效学有利于真菌性呼吸道感染的治疗。
