This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Newman, E. M. Articles by Doroshow, J. H. Search for Related Content PubMed PubMed Citation Articles by Newman, E. M. Articles by Doroshow, J. H.

Pharmacokinetics and Toxicity of Continuous Infusion (6S)-Folinic Acid and Bolus 5-Fluorouracil in Patients with Advanced Cancer¹

Division of pediatrics [E. M. N.], Department of Medical Oncology and Therapeutics Research [S. A. A., J. S. H., L. A. L., K. A. M., R. W. M., J. W. R., G. S., J. H. D.], and Department of Biostatistics [C. A.], City of Hope Cancer Research Center, Duarte, California 91010

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 µM, 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 µM, more than the 4-fold increase predicted by linear pharmacokinetics, while the concentration of (6S)-5-methyltetrahydrofolate was only 16.5 µM. 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.

¹ Supported by NIH Grants CA38053 and CA33572 and by the American Cyanamid Co., Lederle Laboratories, Pearl River, NY. A preliminary report of these results has been presented (J. H. Doroshow et al., Proc. Am. Soc. Clin. Oncol., 10: 97, 1991).

² To whom requests for reprints should be addressed, at Division of Pediatrics, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010.

Received 9/23/91. Accepted 2/25/92.

This article has been cited by other articles:

				J. Jolivet, A. Dayan, M. Beauchemin, D. Chahla, A. Mamo, and R. Bertrand Biochemical and Molecular Studies of Human Methenyltetrahydrofolate Synthetase Oncologist, August 1, 1996; 1(4): 248 - 253. [Abstract] [Full Text] [PDF]

				J Jolivet, A Dayan, M Beauchemin, D Chahla, A Mamo, and R Bertrand Biochemical and molecular studies of human methenyltetrahydrofolate synthetase Stem Cells, January 1, 1996; 14(1): 33 - 40. [Abstract]