Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers
Pulmonary Disposition of Tedizolid following Administration of Once-Daily Oral 200-Milligram Tedizolid Phosphate in Healthy Adult Volunteers
复制标题
DOI：
10.1128/aac.05354-11
复制
发表时间：
2012-05-01
影响因子：
4.9
通讯作者：
Nicolau, David P.
中科院分区：
文献类型：
--
作者：
Housman, Seth T.;Pope, J. Samuel;Nicolau, David P.
本研究评估了接受200 mg前药磷酸替地唑胺口服给药（每24 h一次，持续3天）至稳态的成年志愿者中替地唑胺（一种恶唑烷酮）的肺部处置。在给药间隔期间采集血浆样本，并将参与者随机分配至末次给药后2、6、12或24 h接受支气管肺泡灌洗（BAL）。采用液相色谱-串联质谱法（LC-MS/MS）测定血浆、BAL液和肺泡巨噬细胞（AM）中的药物浓度，并采用尿素校正法计算上皮衬里液（ELF）浓度。通过非房室方法估计药代动力学参数，然后进行房室群体药代动力学。渗透率计算为ELF和AM在给药间隔期间的浓度-时间曲线下面积（AUC（0-24））相对于血浆中游离AUC（0-24）（fAUC（0-24））。血浆中的半衰期和分布容积分别为9.23 +/- 2.04 h和108.25 +/- 20.53 L（平均值+/-标准差）。血浆中的总AUC（0-24）为25.13 +/- 5.78 μ g。h/ml。蛋白结合率为89.44% +/-1.58%，导致平均fAUC（0-24）为2.65 +/- 0.72 μ g。h/ml。ELF中2、6、12和24 h的平均浓度（μ g/ml）分别为9.05 ± 3.83、4.45 ± 2.18、5.62 ± 1.99和1.33 ± 0.59，ELF中分别为3.67 ± 1.02、4.38 ± 2.18、1.42 ± 0.63、AM为1.04 +/- 0.52。ELF和AM渗透率分别为41.2和20.0。人群分析后的平均ELF渗透率为39.7。本研究表明，替地唑胺渗透到ELF和AM中的水平分别约为血浆中游离药物暴露量的40倍和20倍。
This study assessed the pulmonary disposition of tedizolid, an oxazolidinone, in adult volunteers receiving 200 mg of the prodrug tedizolid phosphate orally every 24 h for 3 days to steady state. Plasma samples were collected over the dosing interval, and participants were randomized to undergo bronchoalveolar lavage (BAL) at 2, 6, 12, or 24 h after the last dose. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods followed by compartmental population pharmacokinetics. Penetration was calculated as the area under the concentration-time curve during the dosing interval (AUC(0-24)) for ELF and AM relative to the free AUC(0-24) (fAUC(0-24)) in plasma. The half-life and volume of distribution in plasma were 9.23 +/- 2.04 h and 108.25 +/- 20.53 liters (means +/- standard deviations), respectively. Total AUC(0-24) in plasma was 25.13 +/- 5.78 mu g . h/ml. Protein binding was 89.44% +/- 1.58%, resulting in a mean fAUC(0-24) of 2.65 +/- 0.72 mu g . h/ml in plasma. Mean concentrations (mu g/ml) at 2, 6, 12, and 24 h were 9.05 +/- 3.83, 4.45 +/- 2.18, 5.62 +/- 1.99, and 1.33 +/- 0.59 in ELF and 3.67 +/- 1.02, 4.38 +/- 2.18, 1.42 +/- 0.63, and 1.04 +/- 0.52 in AM. ELF and AM penetration ratios were 41.2 and 20.0. The mean ELF penetration ratio after population analyses was 39.7. This study demonstrates that tedizolid penetrates into ELF and AM to levels approximately 40-fold and 20-fold, respectively, higher than free-drug exposures in plasma.