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

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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.