STUDIES TO INCREASE THE ANTITUMOR ACTIVITY OF 1-(TETRAHYDRO-2-FURANYL)-5-FLUOROURACIL AND ITS METABOLIC ASPECTS BY COMBINED ADMINISTRATION WITH L-CYSTEINE
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概要
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The plasma and liver concentrations of both 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and 5-fluorouracil (5-FU), an active metabolite of FT, increased very markedly after administration of FT (500 mg/kg, p.o.) combined with L-cysteine (L-CYS, 500 mg/kg, i.p. or p.o.) when compared to FT alone in rats. On the other hand, the oral acute toxicity of FT was also enhanced with the combined administration of FT and L-CYS. There was no difference in the in situ absorption rate of FT from the small intestine between rats treated with L-CYS (500 mg/kg, i.v.) and vehicle-treated controls. The inhibition of the disappearance of FT and the increase of the formation of 5-FU was observed in vitro after incubation of FT with liver microsomes from rats treated with L-CYS (500 mg/kg, p.o.) when compared to vehicle-treated controls. The presence of L-CYS significantly inhibited the in vitro degradation of 5-FU by non-treated rat liver homogenate. In the drug metabolizing enzyme activity of rat liver microsomes, aniline <I>p</I>-hydroxylase activity was inhibited, but aminopyrine N-demethylase activity was conversely activated by the combined administration of FT and L-CYS, but not by FT alone; furthermore, no change of cytochrome P-450 content was observed. In sarcoma 180 bearing mice, the oral antitumor activity of FT in combination with L-CYS (500 mg/ kg, i.p. or p.o.) was about 1.1-2.0 times higher than that of FT alone. It was concluded from these findings that the drug metabolizing enzymes in liver involved in the conversion of FT into an active metabolite, 5-FU, are influenced by the combined administration of FT and L-CYS to give an increased organ level of 5-FU; and this resulted in the enhancement of the antitumor activity of FT.
- 社団法人 日本薬理学会の論文
著者
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Kitagawa Haruo
Laboratory Of Biochemical Pharmacology And Biotoxicology Department Of Drug Evaluation And Toxicolog
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Satoh Tetsuo
Laboratory Of Biochemical Pharmacology And Biotoxicology Department Of Drug Evaluation And Toxicolog
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KAWABATA Nobuo
Central Research Laboratory, SS Pharmaceutical Co., Ltd.
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SUGIYAMA Seiyu
Central Research Laboratory, SS Pharmaceutical Co., Ltd.
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KUWAMURA Tsukasa
Central Research Laboratory, SS Pharmaceutical Co., Ltd.
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KITAGAWA Haruo
Laboratory of Biochemical Pharmacology and Biotoxicology, Department of Drug Evaluation and Toxicological Sciences, Faculty of Pharmaceutical Sciences, Chiba University
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KITAGAWA Haruo
Laboratory of Biochemical Pharmacology and Biotoxicology
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SATOH Tetsuo
Laboratory of Biochemical Pharmacology and Biotoxicology
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