Abstract-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 enhance ment of the antitumor activity of FT.

Abstract-Inhibition of rat liver microsomal carboxylesterase(CEase) by 0-ethyl 0-p nitrophenyl phenylphosphonothioate (EPN) and binding of EPN oxygen analog to microsomal CEase were enhanced by addition of NAD or NADP. This was more prominent in addition of NAD than NADP. No potentiation of anti-CEase action of EPN by NAD was seen when pure esterase (E.C. 3.1

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Abstract-Addition of liver cytosol from 16 hr-starved rats treated with 6-aminonicotinamide to rat liver microsomes caused potentiation of the anti-carboxylesterase action of ethyl-p-nitrophenyl phenylphosphonothioate (EPN). This was not found when liver cytosol from non-pretreated rats after 16 hr-starvation was used. This potentiation of EPN-induced inhibition of carboxylesterase may be, at least in part, explained by the fact that treatment of rats with 6-aminonicotinamide resulted in a significant increase in NADPH level in liver cytosol which, in turn, stimulated formation of an EPN oxygen analog, a potent inhibitor of carboxylesterase, through cytochrome P-450-coupled monooxygenase.

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