Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients on a dose escalation schedule

C. J. Van Groeningen, H. M. Pinedo, J. Heddes, R. M. Kok, A. P J M De Jong, E. Wattel, G. J. Peters, J. Lankelma

Research output: Contribution to journalArticlepeer-review

Abstract

The pharmacokinetics of 5-fluorouracil (5-FUra) was investigated in 21 patients with advanced cancer (mainly colorectal cancer). 5-FUra was administered as weekly i.v. bolus injections usually at a starting dose of 500 mg/m2. Every 4 weeks the dose was escalated by 20% until dose-limiting toxicity was observed. Whenever possible, pharmacokinetic studies were performed at dose escalation. 5-FUra plasma concentrations were measured by high pressure liquid chromatography and a sensitive gas chromatography-mass spectrometry assay with a sensitivity as low as 3 x 10-9 M. According to the 42 plasma concentration versus time curves, in all but one of the patients total body clearance decreased with increasing 5-FUra doses, consistent with the nonlinear pharmacokinetics of 5-FUra. The ultrasensitive assay revealed an almost horizontal phase in the plasma concentration versus time curves at plasma concentrations of 10-8 to 10-9 M. This plateau did not show correlation with the area under these curves. The use of a logistic regression method showed that clinical toxicity was correlated with the area under the plasma concentration versus time curve of 5-FUra.

Original languageEnglish (US)
Pages (from-to)6956-6961
Number of pages6
JournalCancer Research
Volume48
Issue number23
StatePublished - 1988
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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