A mathematical model of the kinetics of 5-fluorouracil and its catabolites in freshly isolated rat hepatocytes.

A mathematical model for the kinetics of 5-fluorouracil (FUra) catabolism in liver cells is proposed. It is based on published data for the metabolism of FUra by isolated rat hepatocytes. The model relies on biochemical knowledge of the catabolic pathway. The key-steps are: the cellular uptake and the conversion of the unchanged drug to dihydrofluorouracil (FUH2) and subsequently to alpha-fluoro-beta-alanine (FBAL); the cellular fluxes of the 2 catabolites, FUH2 and FBAL. Water is partitioned between the extracellular and intracellular spaces. The first step is described by Michaelis-Menten kinetics and the other processes by first-order kinetics. Satisfactory fitting of the model validates these simplifications and provides values for the parameters describing the process. The model indicates that the kinetics of FUra disappearance are non linear, the Vmax of the first step being between 3.1 and 5.0 microM/min and the Km between 12 and 37 microM; the rate limiting step is the degradation of FUH2 (the major intracellular catabolite) with a rate constant of 0.1 to 0.02 min-1; the FUH2 transmembrane exchange is active; the exchange of the final catabolite FBAL is by diffusion.