Circadian rhythm of 5-fluorouracil (FU) pharmacokinetics and tolerance

In 28 adult patients with unresectable, disseminated gastrointestinal cancer FU pharmacokinetics as well as hematological and gastrointestinal side-effects of the therapy were evaluated to determine it they were circadian-stage dependent. FU was given as a bolus i.v. injection (15 mg/kg) 4 times at 0100, 0700, 1300, and 1900 at intervals of at least 96h in a changing sequence. Pharmacokinetic parameters were calculated on the basis of drug concentration in the serum, measured by the gas-chromatography method. Hematological side-effects were evaluated on the basis of white blood cell and thrombocyte count. Gastrointestinal toxicity (nausea, vomiting and diarrhoea graded in own 0-2 scale) was evaluated after the therapy. The single-cosinor analysis was applied for both detection and characterization of circadian rhythms. The results of the study were as follows: 1. Pharmacokinetic parameters of FU depend on the time of injection with the highest drug biotransformation at midday and early afternoon. 2. The highest white blood cell count following FU administration was noted after the night injection (0100), though the time of administration did not affect thrombocyte count and gastrointestinal side-effects.