Comparative physiologic dispositions of 5-fluoro-2'-deoxyuridine and 5-fluorouracil in mice bearing solid L1210...

The physiologic disposition of 5-fluoro-2'-deoxyuridine (FUdR) and its metabolites, in particular the postulated active metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), has been studied in BDF1 mice bearing 6-day solid L1210 lymphocytic leukemia between 2 and 72 hours after a single iv dose of 14C-2-FUdR at 380 or 760 mg/kg (400-1300 microcuries/kg). FUdR itself was rapidly eliminated from tissues by urinary excretion and metabolism. However, its metabolites, including 5-fluorouracil (FU), persisted for 72 hours in the acid-soluble and -insoluble fractions of tissues. In tumor and small intestine, 60% of the 0- and 72-hour exposure to FdUMP, based on the area under the concentration-time curve, occurred between 24 and 72 hours after dosing. The results are compared with the physiologic disposition of FU after administration at 200 mg/kg iv which is an equimolar dose to FUdR at 380 mg/kg and approximately equitoxic to FUdR at 760 mg/kg. The molar concentrations of total drug equivalents, and of FU itself, after FUdR at 760 mg/kg were comparable to those after FU. However, the concentrations of FdUMP were lower than after FU, whereas the concentrations of drug equivalents incorporated into the acid-insoluble fraction, which includes equivalents incorporated into RNA, were generally higher than after FU. These data are correlated with the comparative antitumor effects and toxicity in mice of the fluorinated pyrimidines and with their clinical effectiveness.