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 suggested previously that FBAL and/or its metabolites may have a role in the hepatotoxicity, neurotoxicity and cardiotoxicity resulting from FUra chemotherapy. Studies in patients and experimental animals have demonstrated that FBAL has a prolonged elimination compared with the parent drug, FUra. In the present manuscript, a mathematical model is developed 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: 113-119, 1992). Satisfactory agreement was achieved between predicted and measured values, permitting an accurate evaluation of the kinetic and distribution parameters for FBAL. This model indicates that: (1) FBAL accumulates in several tissues including brain, heart, spleen, and enterohepatic system; and (2) enterohepatic circulation of FBAL and its bile acid conjugates has an important role in FBAL kinetics and distribution as demonstrated by a model in which enterohepatic circulation parameters were deleted.
Department of Pharmacology, University of Alabama, Birmingham 35294.
R
R
Zhang
T
T
Liu
S J
SJ
Soong
R B
RB
Diasio
D000818:Animals; D001825:Body Fluid Compartments; D004764:Enterohepatic Circulation / Q000502:physiology; D005472:Fluorouracil / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008432:Mathematical Computing; D008954:Models, Biological; D051381:Rats; D012044:Regression Analysis; D014018:Tissue Distribution; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
D015091:beta-Alanine; C032348:alpha-fluoro-beta-alanine; D005472:Fluorouracil