Population pharmacokinetic modeling of cefadroxil renal transport in wild-type and Pept2 knockout mice.
Population pharmacokinetic modeling of cefadroxil renal transport in wild-type and Pept2 knockout mice.
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DOI：
10.3109/00498254.2015.1080881
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Smith DE
中科院分区：
文献类型：
--
作者：
Xie Y;Shen H;Hu Y;Feng MR;Smith DE
头孢羟氨苄是一种广谱β-内酰胺类抗生素，广泛用于治疗各种感染性疾病。目前，对药物的药代动力学特征和处置机制的了解不足，妨碍了确定最佳剂量方案和在患者中实现理想的抗菌反应。在目前的回顾性研究中，我们开发了一个群体的头孢羟氨苄在野生型和Pept 2基因敲除小鼠使用NONMEM方法的药代动力学模型。头孢羟氨苄的药代动力学最好用二室模型来描述，具有进入/离开中央室的饱和和非饱和消除过程。通过这种建模方法，分别很好地估计了野生型和Pept 2敲除小鼠中的药代动力学参数，如下：中央室容积V1（3.43与4.23 mL），外周室容积V2（5.98 vs. 8.61 mL）、隔室间清除率Q（0.599 vs. 0.586 mL/min）和线性消除速率常数K10（0.111 vs. 0.070 min−1）。此外，分泌动力学（即，Vm 1 = 17.6 nmoL/min和Km 1 = 37.1 μM）和重吸收动力学（即，Vm 2 = 15.0 nmoL/min和Km 2 = 27.1 μM）的头孢羟氨苄在肾脏中的定量，这是首次在体内条件下进行的。我们的模型提供了一个独特的工具，定量预测头孢羟氨苄的剂量依赖性非线性处置，以及潜在的转运介导的药物相互作用。
Cefadroxil is a broad-spectrum β-lactam antibiotic that is widely used in the treatment of various infectious diseases. Currently, poor understanding of the drug’s pharmacokinetic profiles and disposition mechanism(s) prevents determining optimal dosage regimens and achieving ideal antibacterial responses in patients. In the present retrospective study, we developed a population pharmacokinetic model of cefadroxil in wildtype and Pept2 knockout mice using the NONMEM approach. Cefadroxil pharmacokinetics were best described by a two-compartment model, with both saturable and nonsaturable elimination processes to/from the central compartment. Through this modeling approach, pharmacokinetic parameters in wildtype and Pept2 knockout mice were well estimated, respectively, as: volume of central compartment V1 (3.43 vs. 4.23 mL), volume of peripheral compartment V2 (5.98 vs. 8.61 mL), inter-compartment clearance Q (0.599 vs. 0.586 mL/min), and linear elimination rate constant K10 (0.111 vs. 0.070 min−1). Moreover, the secretion kinetics (i.e., Vm1 = 17.6 nmoL/min and Km1 = 37.1 μM) and reabsorption kinetics (i.e., Vm2 = 15.0 nmoL/min and Km2 = 27.1 μM) of cefadroxil were quantified in kidney, for the first time, under in vivo conditions. Our model provides a unique tool to quantitatively predict the dose-dependent nonlinear disposition of cefadroxil, as well as the potential for transporter-mediated drug interactions.