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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)
 
 
 
 
 

Role of administration route in the therapeutic efficacy of doxifluridine.

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 X min, respectively. Antitumor activity and pharmacokinetic results obtained in this model system indicated that 5'-dFUrd is an active agent that can produce cures regardless of the route of administration employed and 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.[1]

References

  1. Role of administration route in the therapeutic efficacy of doxifluridine. Trave, F., Canobbio, L., Au, J.L., Rustum, Y.M. J. Natl. Cancer Inst. (1987) [Pubmed]
 
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