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5-Fluoro-2'-deoxyuridine Elimination by the Isolated Perfused Rat Liver

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

The influence of dose and hepatic blood flow on the elimination of 5-fluoro-2'-deoxyuridine (FdUrd) by the isolated perfused rat liver were investigated. FdUrd (1–20 mg; 4–81 µmol) was injected into the perfusion reservoir and serial samples were collected for chromatographic determination of plasma FdUrd and 5-fluorouracil concentrations. The decrease in FdUrd concentration from values above 100 µM was linear with time (apparent zero order); at concentrations below 30–40 µM the decline became exponential (apparent first order). Semilogarithmic plots of FdUrd concentration/dose versus time obtained with different doses were not superposable, indicating Michaelis-Menten elimination. At a perfusion rate of 20 ml/min, the apparent V_max and K_m for FdUrd disappearance were 14–19 nmol/ml/min and 161–194 µM, respectively. FdUrd clearance during first-order elimination was 8–11 ml/min. After FdUrd administration, 5-fluorouracil concentration reached 10–15% of the initial FdUrd concentration, then decreased with a half-life of 4–7 min. Fifty-four % of the dose of [2-¹⁴C]FdUrd was converted to ¹⁴CO₂. At a dose of 20 mg, first-order clearance of FdUrd increased from 7 to 12 ml/min as hepatic flow increased from 10 to 30 ml/min. Less than 1% of the dose of [6-³H]-FdUrd was incorporated into macromolecules. It was concluded that hepatic elimination of FdUrd is dependent on both dose and blood flow.

¹ Recipient of a Pharmaceutical Manufacturers Association Foundation Medical Student Research Fellowship. Present address: Department of Ophthalmology, Washington University, St. Louis, MO 63110.

² Present address: Department of Pharmacology, Fox Chase Cancer Center, Philadelphia, PA 19111.

³ Recipient of an Amoco Foundation Graduate Student Fellowship. Present address: Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, NIH, Bethesda, MD 20892.

⁴ To whom requests for reprints should be addressed, at the Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY 40292.

Received 9/28/87. Revised 2/11/88. Accepted 3/24/88.