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Activation of Ftorafur [R,S-1-(Tetrahydro-2-furanyl)-5-fluorouracil] to 5-Fluorouracil and -Butyrolactone¹

Departments of Pharmacy and Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, California 94143

The metabolic cleavage of Ftorafur (FT) at the N-1—C-2' position to form 5-fluorouracil (FUra) and -butyrolactone (GBL) as one of the possible products of the tetrahydrofuran moiety was studied in patients and rabbits and in vitro using different enzyme fractions of mouse and rabbit liver homogenates. GBL was identified by gas chromatography and chemical ionization-gas chromatography-mass spectrometry as an FT metabolite generated both in vivo and in vitro. The molar plasma concentrations of GBL, measured by a gas chromatography assay, in two FT-treated patients were severalfold higher than those of the other FT metabolites, measured by high-pressure liquid chromatography, that were previously isolated in humans. Furthermore, pharmacokinetic analysis of the GBL plasma concentrations following GBL and FT doses indicates that 20 to 40% of the administered FT dose was metabolized to GBL in rabbits. Thus, the cleavage of FT to Fura and GBL represents an important pathway of FT activation. In vitro, FT was metabolized to FUra by both the 9000 x g supernatant fraction and the microsomal pellet of mouse liver homogenate; however, GBL was generated only by the 9,000 and 100,000 x g supernatant fractions and not by the microsomal pellets of the mouse and rabbit liver homogenates. These results indicate that there are at least two different metabolic pathways of FT activation to FUra that may involve oxidation at the C-5' position of FT in the microsomal fraction and C-2' or C-5' enzymatic attack in the cytosol fraction. Previously observed FT metabolites that may also serve as intermediates contribute little to the metabolic activation of FT.

¹ This work was supported by USPHS Research Grants GM-16496 from the National Institute of General Medical Sciences, NIH, the Earl C. Anthony Fund from the University of California, San Francisco, and Training Grant GM 00 728-15 from NIH.

² Present address: Department of Experimental Therapeutics, Grace Cancer Drug Center, Rosewell Park Memorial Institute, 666 Elm St., Buffalo, N. Y. 14263.

³ To whom requests for reprints should be addressed.

Received 10/17/79. Accepted 5/ 8/80.