体内过程与药效的关系研究对提高新药研发的成功率至关重要。申请人前期考察了不同药物制剂的药代动力学和组织分布对药效的影响。本项目在此基础上，提出药物结构、组织分布及药效具有相关性。以两组代表性酪氨酸激酶抑制剂类抗肿瘤药物为对象，一类具有相似的结构、相同靶点，但完全不同的作用部位；另一类具有完全不同的结构、相同靶点以及相同作用部位。采用UPLC-MS/MS测定给药后不同时间点的小鼠血浆和组织药物浓度；比较药动学参数，分析每种药物的主要蓄积组织和靶组织，及正常小鼠和肿瘤小鼠的组织分布差异；再利用质谱成像系统进行药物在组织内的定位研究，分析其与肿瘤生长部位的相关性；通过计算机分子模拟，阐明结构的变化如何影响药物的组织分布行为；最终结合药物的临床适应症，明确药物结构、组织分布与药效的关系。本项目的开展，不仅可为研发早期的药物筛选、结构修饰和临床合理用药提供依据，也可为探索新的药物评价体系提供思路。

Studies of the relationships between drug's in vivo process and its efficacy is very important for increasing the success rate of new drug development. Based on the previous studies about pharmacokinetic and tissue distribution of different drug formulations, two types of tyrosine kinase inhibitors (TKIs) are selected in this study. One type of TKIs have similar structures and similar targets, yet they have different clinical indications to treat different cancer; the other type of TKIs have different structures and similar targets, and they have similar clinical indications. UPLC-MS/MS is employed to determine the drug concentration in plasma and tissues at different time points. The pharmacokinetic parameters are compared, to clarify the tissue accumulation and target tissue, and to explain the difference between tissue distribution of normal and tumor mouse model. Then, MALDI-MSI is used to measure the distribution of drugs within tissue sections, relating with the tumor growth. Furthermore, molecular simulation is utilized to clarify the influence of small changes in chemical structure on the tissue distribution. Finally, combined with the efficacy and observed adverse effects, the relationships between chemical structure, tissue distribution and drug efficacy are established. These presented studies will provide not only a tutorial to the clinical use of TKIs and the structure modification of new TKIs, but also the development of new drug evaluation system.