A MATHEMATICAL-MODEL OF THE KINETICS AND TISSUE DISTRIBUTION OF 2-FLUORO-BETA-ALANINE, THE MAJOR CATABOLITE OF 5-FLUOROURACIL

2-Fluoro-beta-alanine (FBAL) is the major metabolite of 5-fluorouracil (FUra), one of the most widely used anticancer drugs. It has been sug gested previously that FBAL and/or its metabolites may have a role in the hepatotoxicity, neurotoxicity and cardiotoxicity resulting from FU ra chemotherapy. Studies in patients and experimental animals have dem onstrated that FBAL has a prolonged elimination compared with the pare nt drug, FUra. In the present manuscript, a mathematical model is deve loped for the kinetics and tissue distribution of FBAL. This model is based on recently published data from a study of the pharmacokinetics and disposition of FBAL in rats (Zhang et al., Drug Metab Dispos 20: 1 13-119, 1992). Satisfactory agreement was achieved between predicted a nd measured values, permitting an accurate evaluation of the kinetic a nd distribution parameters for FBAL. This model indicates that: (1) FB AL accumulates in several tissues including brain, heart, spleen, and enterohepatic system; and (2) enterohepatic circulation of FBAL and it s bile acid conjugates has an important role in FBAL kinetics and dist ribution as demonstrated by a model in which enterohepatic circulation parameters were deleted.