Studies to increase the antitumor activity of 1-(tetrahydro-2-furanyl)-5-fluorouracil and its metabolic aspects by combined administration with L-cysteine.
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 p-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.
D000042:Absorption; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000378:metabolism; D001711:Biotransformation; D003545:Cysteine / Q000494:pharmacology*; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000097:blood; D007700:Kinetics; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D005641:Tegafur / Q000008:administration & dosage* / Q000378:metabolism
D000970:Antineoplastic Agents; D005641:Tegafur; D003545:Cysteine; D005472:Fluorouracil