Murakami Y, Fujii H, Ichimura A, Murata A, Yamashita N, Takagi H, Tauchi K
Medical Research Laboratories, Lederle Japan, Ltd., Saitama, Japan.
J Toxicol Sci. 1998 May;23 Suppl 1:11-29. doi: 10.2131/jts.23.supplementi_11.
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 Cmax and AUC0-infinity. 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.
为了阐明左亚叶酸钙（1-LV）是否会增强5-氟尿嘧啶（5-FU）的毒性，在大鼠中进行了一项为期4周的毒性研究，研究5-FU（10 mg/kg/天）与1-LV（6、20或60 mg/kg/天）联合使用的情况。在单独使用5-FU的组中，检测到体重增加、食物摄入量、红细胞参数和白细胞计数下降。组织病理学检查发现，淋巴器官出现淋巴细胞耗竭、脾脏造血增强和骨髓抑制。在5-FU与1-LV联合使用的组中，红细胞计数下降，髓外造血增加，淋巴器官的抑制增强。在1-LV剂量为20 mg/kg/天及以上时，观察到淋巴器官的变化。在第1次和第14次给药后监测1-LV、1-LV的代谢产物5-甲基四氢叶酸和5-FU的血药浓度时，单独使用5-FU和5-FU与1-LV联合使用在Cmax和AUC0-无穷大方面没有明显差异。1-LV对5-FU毒性的增强作用似乎主要是免疫抑制和骨髓抑制，这与5-FU的抗肿瘤活性有关。本研究中5-FU和1-LV的血浆浓度超过了在体外添加1-LV时观察到由于5-FU导致胸苷酸合成酶（TS）抑制增强的浓度。因此，推测同时给予1-LV导致5-FU的毒性增强与三元复合物（FdUMP-TS-5,10-亚甲基四氢叶酸）形成增加和TS抑制程度更大有关。
