著者

村上 善紀 Fujii Hisako Ichimura Akitoshi MURATA Akiko YAMASHITA Noriaki TAKAGI Hidetoshi TAUCHI Kiyonori

出版者

日本毒性学会

雑誌

Journal of toxicological sciences (ISSN:03881350)

巻号頁・発行日

vol.23, pp.11-29, 1998-05-09

参考文献数

19

被引用文献数

1

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To clarify whether levofolinate calcium (1-LV) enhances 5-fluorouracil (5-FU) toxicity, a 4-week toxicity study of 5-FU (10 mg/kg/day) in combination with 1-LV (6, 20 or 60 mg/kg/day) was conducted in rats. In the 5-FU alone group, a decrease in body weight gain, food consumption, RBC parameter and WBC counts were detected. Histopathologically, lymphoid depletion of lymphatic organs, hematopoiesis enhancement of the spleen and myelosuppression were observed. In the group for which 5-FU was combined with 1-LV, the RBC counts decreased, extramedullary hematopoiesis increased and the suppression of lymphatic organs was enhanced. Changes in the lymphatic organs were observed at 20 mg/kg/day of 1-LV and above. In monitoring of blood drug concentrations of 1-LV, 5-methyl tetrahydrofolic acid, a metabolite of 1-LV, and 5-FU after the 1st and 14th dosings, there was no apparent difference between 5-FU alone and 5-FU combined with 1-LV in C_<max> and AUC_<0-∞>. The potentiation induced by 1-LV in the toxicity of 5-FU appeared to be mainly immuno-suppression and myelosuppression, which were related to the anti-tumor activity of 5-FU. Plasma concentrations of 5-FU and 1-LV in this study overwhelmed the concentrations that enhancement of thymidylate synthetase (TS) inhibition due to 5-FU was observed by addition of 1-LV in vitro. Therefore toxic potentiation of 5-FU due to simultaneous 1-LV dosing is presumed to be concerned with an increased ternary complex (FdUMP-TS-5, 10-methylenetetrahydrofolate) formation and a greater extent of TS inhibition.