Dose and flow dependence of 5-fluorouracil elimination by the isolated perfused rat liver

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 chromatographicall...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1987-10, Vol.47 (20), p.5261-5265
Main Authors: WARREN, B. S, LACRETA, F. P, KORNHAUSER, D. M, WILLIAMS, W. M
Format: Article
Language:English
Subjects:
Animals
Antineoplastic agents
Biological and medical sciences
Dose-Response Relationship, Drug
Fluorouracil - pharmacokinetics
General aspects
Kinetics
Liver - blood supply
Liver - metabolism
Medical sciences
Perfusion
Pharmacology. Drug treatments
Rats
Regional Blood Flow
Time Factors
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Summary: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.
ISSN:0008-5472
1538-7445