Stereoselective metabolism of ftorafur (R,S-1-(tetrahydro-2-furanyl)-5-fluorouracil)

The metabolism of R and S isomers of ftorafur (FT) was studied in vivo and in vitro. FT and its metabolites, i.e., hydroxylated derivatives, (OH-FT), γ-butyrolactone (GBL), 5-fluorouracil (FU), and dehydro-FT, were analyzed by gas chromatography and high-pressure liquid chromatography. Although previous results did not demonstrate any differences in the biological activity of the FT isomers, R- and S-FT were metabolized to different extents by individual pathways. Cleavage of R-FT at the N₁-C_2′ position to form GBL by non-microsomal soluble enzymes in mouse and rabbit liver homogenates was greater than that of S-FT. Following IP administration of S-FT, both cis- and trans-4′-OH-FT were recovered in 24-h rat urine; however, significantly less trans-4′-OH-FT and no cis-4′-OH-FT was detected following R_FT administration. There were no glucuronide or sulfate conjugates of these OH-FT metabolites. These results indicate that urinary hydroxylated metabolites generated from racemic FT consist predominantly of α-l-4′-OH-FT and β-l-4′-OH-FT, and only a small fraction of the trans-4′-OH-FT appears in the β-d configuration of natural nucleosides, confirming earlier reports. The low extent of urinary excretion of hydroxylated FT metabolites in the β-configuration suggests that either there is stereoselective hydroxylation of S-FT or the hydroxylated metabolites with the natural β-d configuration generated from R-FT were preferentially further metabolized prior to excretion into urine. A sample of chemically synthesized β-d-4′-OH-FT was quantitatively converted to FU by thymidine phosphorylase in vitro; this compound may represent a potential FU prodrug.