title: Dose and time dependencies of 5-fluorouracil pharmacokinetics.
abstract: OBJECTIVE
  The purpose of this study was to examine the interpatient and intrapatient variability of the Michaelis-Menten plasma parameters of 5-fluorouracil administered according to a schedule combining a bolus of 400 mg/m2 followed by 22-hour infusion of 600 mg/m2 for 2 consecutive days.
  
  
  METHODS
  A pharmacokinetic population approach was used to analyze the data from 21 patients with colorectal cancer.
  
  
  RESULTS
  The 5-fluorouracil plasma concentrations versus time were best described by a two-compartment model with nonlinear elimination from the central compartment. The relationships between the pharmacokinetic parameters and patient characteristics were tested. On day 1 the mean values (with interindividual variability as expressed by the coefficient of variation) were 1390 mg x h(-1) (20%), and 5.57 mg x L(-1) (22%) for the maximum rate of elimination, and the half-saturating plasma concentration. The maximum rate of elimination was positively correlated to the body surface area and the percentage of liver involvement by metastatic disease determined by tomodensitometric examination. The model was successfully tested with independent data sets corresponding to other schedules. The analysis of this intrapatient variability showed that the half-saturating plasma concentration increased from day 1 to day 2, especially in the patients with low lymphocyte cell dihydropyrimidine dehydrogenase activity.
  
  
  CONCLUSIONS
  The pharmacokinetic parameters obtained in this study would be useful to predict the 5-fluorouracil plasma concentrations following other schedules of administration of 5-fluorouracil and to study the possible pharmacokinetic interactions between 5-fluorouracil and other drugs.
authors.affiliation: Institut Claudius-Regaud and Université Paul-Sabatier, Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Terret
authors.forename: E
authors.initials: E
authors.lastname: Erdociain
authors.forename: R
authors.initials: R
authors.lastname: Guimbaud
authors.forename: M
authors.initials: M
authors.lastname: Boisdron-Celle
authors.forename: H L
authors.initials: HL
authors.lastname: McLeod
authors.forename: R
authors.initials: R
authors.lastname: Féty-Deporte
authors.forename: T
authors.initials: T
authors.lastname: Lafont
authors.forename: E
authors.initials: E
authors.lastname: Gamelin
authors.forename: R
authors.initials: R
authors.lastname: Bugat
authors.forename: P
authors.initials: P
authors.lastname: Canal
authors.forename: E
authors.initials: E
authors.lastname: Chatelut
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000494:pharmacology; D008113:Liver Neoplasms / Q000556:secondary; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D013997:Time Factors
chemical_list: D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil