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首页> 外文会议>Annual International Conference of the IEEE Engineering in Medicine and Biology Society >A Physiologically-Based Pharmacokinetic Model of Methotrexate Incorporating Hepatic Excretion via Multidrug-Resistance-Associated Protein 2 (Mrp2) in Mice, Rats, Dogs, and Humans
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A Physiologically-Based Pharmacokinetic Model of Methotrexate Incorporating Hepatic Excretion via Multidrug-Resistance-Associated Protein 2 (Mrp2) in Mice, Rats, Dogs, and Humans

机译：通过小鼠，大鼠，狗和人类，通过多药抗性相关蛋白2（MRP2）掺入肝细胞排泄的生理学上的药代动力学模型

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An updated physiologically-based pharmacokinetic (PBPK) model of methotrexate (MTX) was built based on an earlier model developed by Bischoff et al. (1971). MTX has been known to be a substrate of multidrug-resistance-associated protein 2 (Mrp2). A three-dimensional quantitative structure-activity relationship model (3D-QSAR) of Mrp2 was developed by Hirono et al. (2005). In our updated PBPK model of MTX, using the computational chemistry-derived binding affinity (K_m), a Mrp2-mediated biliary excretion process was incorporated as the MTX excretory pathway. Our model simulation results are consistent with numerous datasets obtained from mice, rats, dogs, and humans, at a variety of dose levels. Comparisons were made between our updated PBPK model and the earlier one from Bischoff et al. using a PBPK Index approach. Our new PBPK model was further verified against additional pharmacokinetic datasets from rats under special experimental conditions (cannulated bile duct) and Eisai hyperbirilubinemic rats.
机译：基于Bischoff等人开发的早期模型，构建了更新的生理学药代动力学（PBPK）的甲氨蝶甲酸甲酸甲醇（MTX）模型。 （1971）。已知MTX是多药抵抗相关蛋白2（MRP2）的基材。 Hirho等人开发了MRP2的三维定量结构 - 活动关系模型（3D-QSAR）。 （2005）。在我们使用计算化学衍生的结合亲和力（K_M）的MTX的更新的PBPK模型中，将MRP2介导的胆道排泄方法作为MTX排泄途径掺入。我们的模型仿真结果与从小鼠，大鼠，狗和人类获得的许多数据集一起，以各种剂量水平。在我们更新的PBPK模型和比较从Bischoff等人之间进行了比较。使用PBPK索引方法。我们的新PBPK模型进一步验证了特殊实验条件（插管胆管）和Eisai Hyperbirilubine患者的大鼠的另外的药代动力学数据集。

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