Role of Administration Route in the Therapeutic Efficacy of Doxifluridine2

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Abstract
Effect of drug administration route on the therapeutic efficacy of the 5-fluorouracil (FUra) analogue doxifluridine [(5′-dFUrd); 5′-deoxy-5-fluorouridine] was investigated in Fischer CDF rats bearing a chemically induced transplantable colon carcinoma sensitive to fluoropyrimidines. The antitumor activities of 5′-dFUrd and of its parent drug FUra were evaluated after 7 days of continuous administration (by iv infusion, iv push, or po route) of doses ranging from 125 to 750 mg 5′-dFUrd/kg/day and from 12.5 to 55 mg FUra/kg/day. At the maximally tolerated dose, 5′-dFUrd (500 mg/kg/day) and FUra (25–35 mg/kd/day) were equally effective in producing cures when treatments were performed by either continuous iv infusion or iv push. 5′-dFUrd was more effective than FUra when these agents were administered orally (82% cures for 5′-dFUrd vs. 30% cures for FUra). Concentrations of 5′-dFUrd and its metabolite FUra in the blood and urine of normal and tumor-bearing rats were determined by high-performance liquid chromatography following administration of 500 mg 5′-dFUrd/kg. Pharmacokinetic studies indicated that at comparable antitumor activity, systemic exposures to FUra derived from 500 mg 5′-dFUrd/kg administered by iv push, orally, or continuous iv infusion were 3.5±1.0, 3.2±1.1, and 1.5±0.3 mM·min, respectively. Antitumor activity and pharmacokinetic results obtained in this model system indicated that 1) 5′-dFUrd is an active agent that can produce cures regardless of the route of administration employed and 2) among the three methods of drug administration tested, comparable tumor-free survival can be achieved by continuous iv infusion of 5′-dFUrd with the concomitant lowest systemic exposure to the cytotoxic metabolite FUra.