A mathematical model of the kinetics and tissue distribution of 2-fluoro-β-alanine, the major catabolite of 5-fluorouracil

doi:10.1016/0006-2952(93)90017-Q

Biochemical Pharmacology

Volume 45, Issue 10, 25 April 1993, Pages 2063-2069

https://doi.org/10.1016/0006-2952(93)90017-Q Get rights and content

Abstract

2-Fluoro-ß-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 hepatotoxidty, 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 Dispos20: 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 add conjugates has an important role in FBAL kinetics and distribution as demonstrated by a model in which enterohepatic circulation parameters were deleted.

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A mathematical model of the kinetics and tissue distribution of 2-fluoro-β-alanine, the major catabolite of 5-fluorouracil

Abstract

Pharmacol Ther

Jpn J Pharmacol

Biochim Biophys Acta

Biochem Pharmacol

Biochim Biophys Acta

Pharmacol Ther

Clinical pharmacology of cancer chemotherapy

Clinical pharmacology of 5-fluorouracil

Clin Pharmacokinet

Biochemical basis for fluorouracil neurotoxicity. The role of Krebs cycle inhibition by fluoroacetate

Arch Neurol

Fluorouracil: Biochemistry and pharmacology

J Clin Oncol

Neuropathologic study on chronic neurotoxicity of 5-fluorouracil and its masked compounds in dogs

Acta Neuropathol (Berl)

Subacute neurotoxicity of 5-fluorouracil and its derivative, carmofur, in cats

Acta Pathot Jpn

Experimental neurotoxicity of 5-fluorouracil and its derivatives is due to poisoning the monofluorinated organic metabolites, monofluoroacetic acid and α-fluoro-β-alanine

Acta Neuropathol (Berl)

Production of cholestasis by 2-fluoro-β-alanine-chenodeoxycholic acid: Possible role of this metabolite in the cholestasis associated with hepatic arterial infusion of fluoropyrimidine