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Dose and Flow Dependence of 5-Fluorouracil Elimination by the Isolated Perfused Rat Liver¹

Departments of Pharmacology and Toxicology [B. S. W., F. P. L., W. M. W.] and Medicine [W. M. W.], University of Louisville, Louisville, Kentucky 40292

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 µM, 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. V_max and K_m were 6–11 nmol/ml/min and 33–45 µM, 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, V_max was unchanged but K_m decreased progressively from 84 to 32 µM, 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.

¹ Preliminary experiments in this investigation were performed at the Department of Pharmacological and Physiological Sciences, University of Chicago, Chicago, IL 60615, where the work was supported by National Cancer Institute Grants CA12599-05 and 1R01-CA25543 (D. M. K.) and a Pharmaceutical Manufacturers Association Foundation Fellowship (W. M. W.).

² Recipient of an Amoco Foundation Graduate Student Fellowship. Present address: Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, Bethesda, MD 20892.

³ Present address: Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111.

⁴ Present address: Department of Medicine, Johns Hopkins University, Baltimore, MD 21205.

⁵ To whom requests for reprints should be addressed, at the Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292.

Received 3/20/87. Revised 7/ 9/87. Accepted 7/14/87.