Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients on a dose escalation schedule.
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 those 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.
van Groeningen
C J
CJ
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Pinedo
H M
HM
Heddes
J
J
Kok
R M
RM
de Jong
A P
AP
Wattel
E
E
Peters
G J
GJ
Lankelma
J
J
D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged
D005472:Fluorouracil