College of Pharmacy, Catholic University of Daegu, Gyeongsan-si, Gyeongbuk, Korea.
Cancer Chemother Pharmacol. 2011 Aug;68(2):465-75. doi: 10.1007/s00280-010-1502-y. Epub 2010 Nov 11.
The objectives of this study were to develop physiologically based models for the pharmacokinetics (PK) and organ distribution of apicidin in rats and mice and to predict human PK in blood and organs.
The PK of apicidin was characterized in rats and mice after i.v. bolus injection, and distribution to various tissues was determined in rats following i.v. infusions at steady state. The developed models were prospectively validated within rat and within mouse and by scaling from rat to mouse using data after multiple i.v. injections. Human PK was predicted by the physiologically based modeling using intrinsic clearance data for humans from in vitro experiments.
The Cl(s) predicted for human (9.8 ml/min/kg) was lower than those found in mice (116.9 ml/min/kg) and rats (61.6 ml/min/kg), and the V(ss) predicted for human (1.9 l/kg) was less than in mice (2.0 l/kg) and rats (2.5 l/kg). Consequently, the predicted t (1/2) was longer in human (2.3 h) than in mice and rats (0.4 and 0.9 h, respectively). The highest concentrations of apicidin were predicted in liver followed by adipose tissue, kidney, lung, spleen, heart, arterial blood, venous blood, small intestine, stomach, muscle, testis, and brain.
The developed models adequately described the PK of apicidin in rats and mice and were applied to predict human PK. These models may be useful in predicting human blood and tissue concentrations of apicidin under different exposure conditions.
本研究旨在建立适用于大鼠和小鼠的棘白菌素药代动力学（PK）和器官分布的基于生理学的模型，并预测人体血液和器官中的 PK。
在大鼠和小鼠中进行静脉推注后，对棘白菌素的 PK 进行了特征描述，并在静脉输注稳态后确定了其在各种组织中的分布。使用多次静脉注射后的数据，通过从大鼠到小鼠的比例缩放，对开发的模型进行了前瞻性验证。使用来自体外实验的人体内在清除率数据，通过基于生理学的建模预测人体 PK。
预测的人体 Cl(s)（9.8 ml/min/kg）低于小鼠（116.9 ml/min/kg）和大鼠（61.6 ml/min/kg），预测的人体 V(ss)（1.9 l/kg）低于小鼠（2.0 l/kg）和大鼠（2.5 l/kg）。因此，预测的人体 t(1/2)（2.3 h）长于小鼠和大鼠（分别为 0.4 和 0.9 h）。棘白菌素的最高浓度预测出现在肝脏，其次是脂肪组织、肾脏、肺、脾脏、心脏、动脉血、静脉血、小肠、胃、肌肉、睾丸和大脑。
开发的模型充分描述了大鼠和小鼠中棘白菌素的 PK，并用于预测人体 PK。这些模型可能有助于预测在不同暴露条件下人体血液和组织中棘白菌素的浓度。
