title: Pharmacokinetics and toxicity of continuous infusion (6S)-folinic acid and bolus 5-fluorouracil in patients with advanced cancer.
abstract: Twenty-seven patients with advanced cancer were entered in a phase I study of bolus i.v. 5-fluorouracil at a dose of 370 mg/m2/day for 5 days combined with a continuous i.v. infusion of (6S)-folinic acid for 5.5 days, starting 24 h in advance of the first 5-fluorouracil dose. The dose of (6S)-folinic acid was escalated in cohorts of patients from 250 mg/m2/day to a maximum of 1000 mg/m2/day. The pharmacokinetics of (6S)-folinic acid were studied in the 3 patients given 250 mg/m2/day and in 6 patients given 1000 mg/m2/day. The mean steady-state plasma concentrations of (6S)-folinic acid and its principal metabolite (6S)-5-methyltetrahydrofolate at the 250 mg/m2/day dose were 2.7 and 5.1 microM, respectively. Both concentrations were comparable to the concentrations produced when (6S)-folinic acid was administered as half of a (6R,S)-folinic acid mixture (E. M. Newman et al., Cancer Res., 49:5755-5760, 1989). At the 1000 mg/m2/day dose of (6S)-folinic acid, the concentration of (6S)-folinic acid was 15.3 microM, more than the 4-fold increase predicted by linear pharmacokinetics, while the concentration of (6S)-5-methyltetrahydrofolate was only 16.5 microM. The change in the ratio of the parent compound to its metabolite was accounted for by a decrease in the nonrenal clearance of (6S)-folinic acid, probably indicating saturation of its metabolism. The toxicities observed in this phase I trial, including stomatitis, diarrhea, neutropenia, and anemia, did not differ in nature or severity from those produced by 5-fluorouracil and (6R,S)-folinic acid when administered on the same schedule. Finally, the degree of toxicity did not appear to depend on the dose of (6S)-folinic acid over the range of doses tested.
authors.affiliation: Division of Pediatrics, City of Hope Cancer Research Center, Duarte, California 91010.
authors.forename: E M
authors.initials: EM
authors.lastname: Newman
authors.forename: S A
authors.initials: SA
authors.lastname: Akman
authors.forename: J S
authors.initials: JS
authors.lastname: Harrison
authors.forename: L A
authors.initials: LA
authors.lastname: Leong
authors.forename: K A
authors.initials: KA
authors.lastname: Margolin
authors.forename: R J
authors.initials: RJ
authors.lastname: Morgan
authors.forename: J W
authors.initials: JW
authors.lastname: Raschko
authors.forename: G
authors.initials: G
authors.lastname: Somlo
authors.forename: C W
authors.initials: CW
authors.lastname: Ahn
authors.forename: J H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*
chemical_list: D002955:Leucovorin; D005472:Fluorouracil