Determination of 1, 3-Bis (Tetrahydro-2-Furany1)-5-Fuluoro-2, 4-Pyrimidinedione and its Metabolites

Abstract

The pyrimidine antimetabolite such as futorafur (FT-207) is widely prescribed in carcinomas of breast and gastrointestinal tract. Since 1972, it has been suggested that FT-207 act through metabolic conversion to 5-FU and represented a chemical depot form of 5-FU. The newly synthesized antimetabolic drug, FD-1, is lipid soluble and believed that it is converted to FT-207 and N-3 compound, respectively. These two chemicals are further converted to 5-FU as the active metabolite for cancer therapy. For the preparation of the program for the treatment of the patients with carcinomas by FD-1, it is essential to estimate the concentration of FD-1 and its metabolites in biological fluides.
A high speed liquid chromatography was developed for the separation and estimation of FD-1 and its metabolites. To solubilize FD-1 in water system, paired ion chromatographic method using PIC^th B7 was applied. On high speed liquid chromatogram, 5-FU, FT-207, N-3 and FD-1 were separated and eluted in this order. The determination of 5-FU with sensitivity of 1ng/ml and of FD-1 with sensitivity of 10ng/ml, respectively. The results have suggested that the method would be sufficient for the clinical studies of these anticancer therapeutics.
The effect of each drug on cellular immunity was estimated individually by means of normal human lymphocyte culture system. For this purpose, the lymphocytes were separated into T and B cells by free flow electrophoresis. The blastogenesis of T cell against each drug was carried out in the presence of phytohemaggultinin-P, and of B cell was performed in the presence of porkweed mitogen. The results suggested that FD-1 as well as FT-207 inhibited the blastogenesis of T cell in the range of 50-60%. But N-3 compound less inhibited than these two. On the other hand, N-3 compound effectively inhibited the blastogenesis of B cell. The descrepancy of the effect of N-3 compound on the blastogenesis between T cell and B cell is not known. The metabolic pathway of FD-1 in vivo and the further metabolic pathway of its metabolites must be elucidated.