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Disposition of 5-Fluorouracil after Intravenous Bolus Doses of a Commercial Formulation to Cancer Patients¹

Departments of Medicine [D. S. S., D. H. S., M. P. T., J. R. R.], Surgery [M. P. T.], and Pharmacology and Therapeutics [D. S. S., J. R. R.], McGill University, The Montreal General Hospital, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada

A high-pressure liquid chromatographic method that is used to determine the pharmacokinetic disposition of 5-fluorouracil from the plasma compartment is presented. The method requires only 0.5 ml of plasma for each determination and is sensitive to 0.1 mg of drug per liter. Novel methodology with the use of an ion-specific electrode technique for the determination of urinary excretion kinetics of 5-fluorouracil and its metabolites is also presented. This study demonstrated a much greater variability for the disposition of 5-fluorouracil by cancer patients than has been reported previously. The apparent volume of distribution for this drug varied more than 37-fold. Its plasma half-life varied more than 19-fold, and its urinary excretion half-life varied almost 400-fold. These data are compatible with the hypothesis that this variation could account, at least in part, for the variable therapeutic and toxic response to 5-fluorouracil. The methodology presented in this study is sufficiently simple and sensitive to allow assessment of this hypothesis by investigating cancer patients who receive therapeutic doses of 5-fluorouracil.

¹ This work was done in the Oncology Center and the Division of Clinical Pharmacology. The Montreal General Hospital, 1650 Cedar Ave., Montreal, Quebec, H3G 1A4, Canada, and has been sponsored by grants from The Cancer Research Society, Incorporated, and The Canadian Foundation for the Advancement of Therapeutics.

² Monat Scholar, McGill University.

Received 3/16/77. Accepted 8/ 8/77.