Zhu Liqin, Zhang Yuan, Yang Jianwei, Wang Yongming, Zhang Jianlei, Zhao Yuanyuan, Dong Weilin
Pharmacy Department, Tianjin First Center Hospital, No. 24 Fukang Road, Nankai District, Tianjin, 300192, China.
Tianjin Medical University, Tianjin, 300070, China.
Eur J Drug Metab Pharmacokinet. 2016 Aug;41(4):395-402. doi: 10.1007/s13318-015-0271-8. Epub 2015 Mar 10.
This study developed a physiologically based pharmacokinetic (PBPK) model in intraabdominally infected rats and extrapolated it to humans to predict the levofloxacin pharmacokinetics and penetration into tissues. Twelve male rats with intraabdominal infections induced by Escherichia coli received a single dose of 50 mg/kg body weight of levofloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480 and 1440 min after injection, respectively. A PBPK model was developed in rats and extrapolated to humans using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration-versus-time profile of levofloxacin in rats, C max was 23.570 μg/ml at 5 min after intravenous injection, and t1/2 was 2.38 h. The plasma concentration and kinetics in humans were predicted and validated by the observed data. Levofloxacin penetrated and accumulated with high concentrations in the heart, liver, kidney, spleen, muscle and skin tissues in humans. The predicted tissue-to-plasma concentration ratios in abdominal viscera were between 1.9 and 2.3. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict the drug pharmacokinetics and penetration in humans. Levofloxacin had good penetration into the liver, kidney and spleen as well as other tissues in humans. This pathological model extrapolation may provide a reference for the study of antiinfective PK/PD. In our study, levofloxacin penetrated well into abdominal organs. Also ADR monitoring should be implemented when using levofloxacin.
本研究在腹腔感染大鼠中建立了基于生理的药代动力学（PBPK）模型，并将其外推至人体，以预测左氧氟沙星的药代动力学及在组织中的渗透情况。十二只由大肠杆菌诱导腹腔感染的雄性大鼠接受了单次剂量为50mg/kg体重的左氧氟沙星。分别在注射后5、10、20、30、60、120、240、480和1440分钟采集血浆。在大鼠中建立了PBPK模型，并使用GastroPlus软件将其外推至人体。通过比较预测值和观察值来评估预测结果。在大鼠左氧氟沙星的血浆浓度-时间曲线中，静脉注射后5分钟时Cmax为23.570μg/ml，t1/2为2.38小时。人体中的血浆浓度和动力学通过观察数据进行预测和验证。左氧氟沙星在人体心脏、肝脏、肾脏、脾脏、肌肉和皮肤组织中高浓度渗透和蓄积。预测的腹部脏器组织与血浆浓度比在1.9至2.3之间。当已知大鼠血浆浓度时，PBPK模型外推是预测药物在人体中药代动力学和渗透情况的一种方法。左氧氟沙星在人体肝脏、肾脏、脾脏以及其他组织中具有良好的渗透性。这种病理模型外推可为抗感染药的药代动力学/药效学研究提供参考。在我们的研究中，左氧氟沙星在腹部器官中渗透性良好。使用左氧氟沙星时还应进行不良反应监测。
