目前针对抗肿瘤药物的药动学模型主要集中于对药物在动物正常组织的分布预测，缺少对其在肿瘤组织分布的模型化预测研究。前期工作表明，对阿霉素在荷瘤小鼠的组织分布预测中，生理药动学模型PBPK只能将肿瘤按均质性组织处理，预测其肿瘤组织的平均浓度。Tumor cord模型可描述药物在血管化肿瘤组织的摄取与分布，但其需要将血药浓度作为输入值，限制了其预测性研究。本课题拟建立一种新的模型方法，搭建tumor cord-PBPK偶联模型，对抗肿瘤药物的药动学进行全面描述。基于搭建的偶联药动学模型，预测抗肿瘤药物在荷瘤小鼠肿瘤组织及其它组织分布情况；将鼠药动学模型种属外推，预测人体药动学；基于模型进行参数敏感性分析，探讨影响药物组织分布的因素；对联合用药后药物的药动学进行预测，指导给药方案设计。该模型有助于揭示抗肿瘤药物在系统水平的药动学与肿瘤组织分布间的关系，对抗肿瘤药物的研究和临床应用具有重要指导意义。

The pharmacokinetic models of antitumor drugs mainly focus on the prediction of drug distribution in normal tissues instead of tumor tissues in animals. We have confirmed that the physiologically based pharmacokinetic model (PBPK) could predict the average concentration of adriamycin in the tissues of tumor bearing mice, treating heterogeneous tumor tissue as homogeneous tissue, inaccurately. While “tumor cord” model could describe the uptake and distribution of drugs in vascularized tumor tissue, this model has limitation in its predictive study, which is lacking plasma concentration as an input value to predict reliably. We intended to establish a new model, coupling the “tumor cord” model with the PBPK model, which will combine the advantages of describing tumor tissues and interpreting systemic distribution of drugs, to predict the pharmacokinetic behavior of antitumor drugs more accurately. Based on this coupling model, distributions of drugs in the tumor tissues and others in the tumor-bearing mice were predicted precisely. Then, the PBPK model in rat was extrapolated to predict the drug pharmacokinetics in human, and the parameter sensitivity was analyzed to evaluate impact factor on the bio-distribution of antitumor drugs. In addition, the pharmacokinetic behaviors of different drugs in chemotherapy, simultaneously, were predicted within coupling model, providing guide of rational dosing regimen. This model will reveal the interaction between pharmacokinetics at the system level and distribution of drugs in tumor, which could improve understanding of antitumor drugs in the experimental study and clinical application.