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Published on: June 30, 2014
Dose and flow dependence of 5-fluorouracil elimination by the isolated perfused rat liver
B S Warren1, F P LaCreta, D M Kornhauser
1Department of Pharmacology and Toxicology, University of Louisville, Kentucky 40292.
Abstract:
The influences of dose and hepatic blood flow on the elimination of 5-fluorouracil (FUra) by the isolated perfused rat liver were investigated. FUra was injected into the perfusion reservoir and then serial blood samples were collected over 2-3 h. FUra concentration was determined chromatographically. In some experiments, the conversion of [2-14C]FUra to 14CO2 was also determined. With livers perfused at 20 ml/min, the initial decrease in plasma FUra concentration was linear with time (apparent zero-order kinetics); at concentrations below about 25 microM, the decrease became exponential (apparent first-order kinetics). Semilogarithmic plots of FUra concentration/dose versus time obtained with different doses were not superposable, consistent with saturable (Michaelis-Menten) elimination. Vmax and Km were 6-11 nmol/ml/min and 33-45 microM, respectively. Hepatic clearance during first-order elimination was close to 20 ml/min. About 84% of the dose was converted to CO2, indicating that catabolic metabolism was the principal route of elimination. As hepatic blood flow increased from 10 to 30 ml/min, Vmax was unchanged but Km decreased progressively from 84 to 32 microM, and clearance increased from 12 to 29 ml/min. It was concluded that hepatic FUra elimination is highly dependent upon both dose and blood flow.
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