title: Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer.
abstract: BACKGROUND
  The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied.
  
  
  METHODS
  One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle.
  
  
  RESULTS
  The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients.
  
  
  CONCLUSIONS
  A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.
authors.affiliation: Oncology Division, Rovigo General Hospital, Rovigo, Italy. milenagusella@libero.it
authors.forename: M
authors.initials: M
authors.lastname: Gusella
authors.forename: G
authors.initials: G
authors.lastname: Crepaldi
authors.forename: C
authors.initials: C
authors.lastname: Barile
authors.forename: A
authors.initials: A
authors.lastname: Bononi
authors.forename: D
authors.initials: D
authors.lastname: Menon
authors.forename: S
authors.initials: S
authors.lastname: Toso
authors.forename: D
authors.initials: D
authors.lastname: Scapoli
authors.forename: L
authors.initials: L
authors.lastname: Stievano
authors.forename: E
authors.initials: E
authors.lastname: Ferrazzi
authors.forename: F
authors.initials: F
authors.lastname: Grigoletto
authors.forename: M
authors.initials: M
authors.lastname: Ferrari
authors.forename: R
authors.initials: R
authors.lastname: Padrini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003710:Demography; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged
chemical_list: D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil