Basic construction of individual administering design method based on clarification of excretion mechanism of topoisomerase I inhibitor

为明确拓扑异构酶I抑制剂伊立替康和拓扑替康的排泄机制，我们采用培养细胞进行转运实验，用大鼠进行清除实验，并对药物转运体hOAT1细胞和hOAT3细胞进行基因外观系统细胞实验。结果表明，大鼠的脏器以羟基酸形态（a - tpt）为弧长，其脏器的弧长依次为肾的弧长为肝的弧长为肺的弧长为肺的弧长为小肠的弧长为心的弧长为脑的弧长为心的弧长为脑的弧长。此外，还提出了一种特殊的有机阴离子运输系统参与了A-TPT的吸收。尽管与载体细胞相比，hOAT3细胞中A-TPT的运输明显促进，但hOAT1细胞的运输不承认这种变化。此外，hOAT1细胞和hOAT3细胞均未促进A-TPT的运输。我们认为OAT3至少部分地参与了A-TPT的转移。利用人培养细胞HL-60中活性氧之一过氧化氢的耐受源HP100细胞和HL-60源，从诱导凋亡的角度评价伊立替康和拓扑替康对器官的损伤。结果提示过氧化氢参与了SN-38和拓扑替康的凋亡，并提示其激活途径为：伊立替康介导DNA裂解→H_20_2升高→线粒体损伤→caspase-3激活→诱导凋亡。计划今后从诱导凋亡的角度评价伊立替康和拓扑替康对器官的损害，建立器官损害的检测方法，并从药代动力学和药效学的角度验证药物转运体在器官损害中的作用。

To clarify excretion mechanisms of irinotecan and topotecan, topoisomerase I inhibitors, we investigated the transportation experiment used the cultured cells, the clearance experiment used the rats, and the gene appearance system cell of the drug transporter (hOAT1 cell and hOAT3 cell) was executed. It was clarified that rat internal organs taking clearance (CL) of hydroxy acid form (A-TPT) of topotecan showed a high, internal organs peculiar distribution in order of kidney≒liver>lungs>small intestines≒heart>brain. In addition, the participation of an organic anion transportation system peculiar was suggested in taking of A-TPT. The change was not admitted in transportation in the hOAT1 cell though the transportation of A-TPT in the hOAT3 cell was remarkably promoted compared with the vector cell. In addition, neither the hOAT1 cell nor the hOAT3 cell were promoted as for the transportation of A-TPT. It was thought that OAT3 at least took part from these results in shift of A-TPT partially.The HP100 cell that was the tolerance stock of hydrogen peroxide that was one of the active oxygen species in human culture cell HL-60 and the HL-60 origin was used of the evaluation of the organ damage by irinotecan and topotecan ftom the viewpoint of the apoptosis induction. As a result, it was suggested that hydrogen peroxide take part in the apoptosis of SN-38 and topotecan, and was suggested the existence of the route in activation, as follows : DNA cleavage by irinotecan→rise in cellar level of H_20_2→mitochondria injury→activation of caspase-3→apoptosis induction.It is scheduled that the organ damage by irinotecan and topotecan is evaluated from the viewpoint of the apoptosis induction in addition, the detection method of the organ damage is established, and the role of the drug transporter in the organ damage is verified from the viewpoint of pharmacokinetics and pharmacodynamics in the future.