COMPARISON OF PHARMACOKINETICS OF 5-FLUOROURACIL AND 5-FLUOROURACIL WITH CONCURRENT THYMIDINE INFUSIONS IN A PHASE-I TRIAL

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  • 1 January 1980
    • journal article
    • research article
    • Vol. 40  (1) , 107-113
Abstract
The serum half-life of 5-fluorouracil (5-FUra) in humans is best described as biexponential decay function, with t1/2 .alpha. = 7.8 .+-. 2.6 min and t1/2 .beta. = 36.8 .+-. 13.5 min during initial courses of this drug alone. Pharmacokinetics of 5-FUra during courses of daily therapy (for 5 days) revealed prolongation of t1/2 in both components of the decay curve, which was not previously reported. Despite the efficacy of thymidine (dThd) given as a continuous i.v. infusion of 8 g/sq m per day in prevention of high-dose methotrexate toxicity, continuous infusion of dThd at this dose does not prevent the toxicity of 5-FUra or reverse inhibition of DNA and RNA synthesis by 5-FUra. On the contrary, continuous infusion of dThd appears to increase the toxicity of 5-FUra in all respects. Pharmacokinetic studies of 5-FUra during continuous dTHd infusion revealed prolongation of the 5-FUra t1/2 which remained stable through the course of 5 days of 5-FUra with dThd. This protracted t1/2 is believed to account at least in part for the increased toxicity of 5-FUra with dThd. Dose-limiting mucositis, myelosuppression and gastrointestinal toxicity were observed at 5-FUra doses of 1/2-2/3 the customarily tolerated dose of 5-FUra alone in similar courses of daily bolus therapy (for 5 days).