Determination of 5-fluorouracil (NSC-19893) plasma levels in rats and man by isotope dilution-mass fragmentography.
A highly sensitive and specific rapid assay for 5-fluorouracil (5-FU) in plasma samples at concentrations as low as 1 ng/ml was developed using mass fragmentography. Highly enriched C14-5-FU was empolyed as an internal standard. A two-compartmental open model for the disposition of free 5-FU in plasma is proposed. The beta-phase of 5-FU plasma elimination describes the pool size of anabolic metabolites, assuming this model is correct. Injections of 5-fu at 15, 40, and 90 mg/kg in rats resulted in an alpha-phase of elimination from plasma with a half-life of 10-18 minutes. The beta-phase could only be measured after the injection of 90 mg/kg of 5-FU and amounted to about 20 hours in two rats. Higher doses resulted in an unproportional increase in 5-FU plasma concentrations in the beta-phase, thus establishing nonlinear kinetics, presumably of the degradative metabolism. Plasma concentrations of 5-FU in man were measured after oral and intravenous administration of 15 mg/kg of 5-FU. Plasma elimination half-lives after intravenous doses were 12 minutes and dropped below measurable levels 2 hours after administration in three patients. After oral administration, peak plasma levels of 5-FU varied between 0.8 and 60 mug/ml of 5-FU in three patients after 10 minutes to 2 hours. Two of these patients showed rapid absorption and a measurable beta-phase of 5-FU plasma elimination possibly indicating a larger anabolic pool size of 5-FU-derived nucleosides and nucleotides when compared to patients receiving intravenous doses. This study may provide a pharmacokinetic rationale to monitor patients receiving 5-FU treatment.
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000818:Animals; D002250:Carbon Radioisotopes; D002849:Chromatography, Gas; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood*; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007700:Kinetics; D008297:Male; D013058:Mass Spectrometry; D008722:Methods; D008875:Middle Aged; D008954:Models, Biological; D011865:Radioisotope Dilution Technique; D051381:Rats
D002250:Carbon Radioisotopes; D005472:Fluorouracil