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The Physiological Disposition of 5-Fluorouracil in Mice Bearing Solid L1210 Lymphocytic Leukemia¹

Life Sciences Division, Arthur D. Little, Inc., Cambridge, Massachusetts 02140

The physiological disposition of 5-fluorouracil (FU) and its metabolites, in particular 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP), has been studied in BDF₁ mice bearing 6-day solid L1210 lymphocytic leukemia up to 72 hr after a single i.v. dose of FU-2-¹⁴C, 200 mg/kg, 300 to 1000 Ci/kg. The drug persisted in all tissues, particularly in tumor, for hours after its elimination from blood. The anabolites of FU similarly persisted in both acid-soluble and acid-insoluble fractions of tissues. In most tissues, the major portion of the 72-hr exposure to FU, 5-fluorouridine, 5-fluorouridine 5'-monosphosphate, and the di- and triphosphates of 5-fluorouridine, based on areas under the concentration-time curves, occurred during the 1st 24 hr after dosing. In some tissues, including tumor and small intestine, the major portion of the 72-hr exposure to the di- and triphosphates occurred between 24 and 72 hr after dosing. In particular, FdUMP, which is believed to be the active metabolite, persisted in significant concentrations in all tissues for 72 hr. In most tissues, over 50% of the 72-hr exposure to FdUMP occurred between 24 and 72 hr after dosing. In tumor, where the highest overall exposure to FdUMP was observed, and in small intestine, 70% of the exposure occurred after 24 hr. The significance of the persistence of the active metabolite is discussed.

¹ This work was supported by Contract PH 43-65-61 with Chemotherapy, National Cancer Institute, NIH.

Received 7/28/71. Accepted 2/16/72.

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