The Pharmacology of Ftorafur (R, S-1-(Tetrahydro-2-Furanyl)-5-Fluorouracil) * J. L. Au and W. Sadee School of Pharmacy and Department of Pharmaceutical Chemistry, University of California San Francisco, USA - San Francisco, CA 94143 Introduction Ftorafur (FT) was synthesized in the Soviet Union in 1966, as part of a program searching for fluorinated pyrimidines with an improved therapeutic index over that of 5-fluorouracil (FU) [29]. It bears structural resemblance to FU and 5-fluorodeoxy- uridine (FUdR), the two fluorinated pyrimidine antimetabolites in clinical use. It has been proposed that FT is metabolically activated in vivo and represents a chemical depot form of FU [12, 20, 21, 25, 34, 46, 47, 54,56]. Clinically, FT has shown activity similar to that of FU, but it is less toxic to the bone marrow [27, 35, 58]. The reduced myelosuppression of FT has prompted clinical trials, first in the Soviet Union and Japan, and more recently in the United States [28]. However, the high neurotoxicity of FT may limit its widespread clinical use in the future [35, 58]. FU undergoes a series of metabolic conversions to its active nucleotides. Due to the complex scheme of activation, the tissue selectivity of FU may depend on a number of biochemical determinants (reviewed by Myers et al. [48] and Sadee and Wong [52] as well as its delivery to the target tissues. For example, when given as a prolonged infusion instead of a bolus injection, FU is less myelosuppressive [48, 52]. The plasma clearance of FU ranges from OA-211kg/h after a bolus injection to 3-60 lIkg/h after an 8 h infusion [10, 16, 17, 39]. The reason for this drastic difference in FU pharmacokinetics is still obscure. When FU is administered in a form of metabolic prodrug, the kinetics of its release may be related to its bone marrow toxicity; moreover, the tissue selectivity is further complicated by the distribution charac- teristics, rate, and mechanism of activation of the FU pro drug , such as FT. Although the clinical trials of FT were started in 1967, its pharmacology has not been fully elucidated. This chapter will review several aspects of its pharmacology, with particular emphasis on the kinetics and mechanism of metabolic activation of FT to FU. Chemical Classification and Synthesis· FT represents a new class of heterocyclic compounds named furanidyl pyrimidines. The structure of FT is shown in Fig. 1 and is compared to those of FU and FU dR. FT is * This work is supported by Public Health Research Grants GM-16496 from NIGMS, the Earl C. Anthony Fund from UCSF, and Training Grant GM 00728-15 from NIH S. K. Carter et al. (eds.), New Drugs in Cancer Chemotherapy © Springer-Verlag Berlin Heidelberg 1981