Summary
As part of a clinical trial of 5-fluorouracil (5-FU) administered as a 24-hour intravenous infusion in patients with colorectal carcinoma, pharmacokinetic studies of (6S)-leucovorin [(6S)-LV] and its major metabolite 5-methyl-tetrahydrofolate (5-CH3-THF) were performed in 8 patients given a continuous intravenous infusion of (6S)-LV 100 mg/m2 followed by 5 oral doses of (6S)-LV 50mg. The aim of this study was to assess whether 5 oral doses of (6S)-LV 50mg administered after intravenous treatment can maintain the plasma concentrations of reduced folates within the range shown to optimise 5-FU cytotoxicity throughout a 24-hour period of 5-FU treatment. The pharmacokinetics of (6S)-LV 50mg administered orally was investigated in 4 additional patients. The mean (± SD) plasma concentrations of (6S)-LV and 5-CH3-THF after 4-hour infusion of (6S)-LV, before 5-FU treatment, were 14.5 ± 3.1 µmol/L and 4.7 ± 2.8 µmol/L, respectively; at 4 hours postinfusion, before starting repeated oral doses, their concentrations were 1.2 ± 0.5 µmol/L and 3.6 ± 1.4 µmol/L, respectively. At 4 hours after a single oral dose of (6S)-LV 50mg, the mean plasma concentrations of (6S)-LV and 5-CH3-THF were 0.4 ± 0.2 µmol/L and 2.7 ± 1.0 µmol/L. (6S)-LV was cleared from plasma more slowly after oral [mean residence time (MRT) = 2.1 ± 0.2 hours] than after intravenous treatment (MRT = 1.5 ± 0.5 hours). At the end of 5-FU treatment, after 5 oral doses of (6S)-LV 50mg, the mean plasma concentrations of total reduced folates [(6S)-LV + 5-CH3-THF] were in the range reported for the synergism with fluoropyrimidines after either intravenous (3.1 ± 0.9 µmol/L) or oral treatment (2.7 ± 0.6 µmol/L).
The present study suggests that a regimen combining a 4-hour continuous infusion followed by repeated oral doses of (6S)-LV is able to maintain modulating plasma concentrations of total bioactive folates throughout a 24-hour continuous infusion of 5-FU.
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References
Arbuck SG. Overview of clinical trials using 5-fluorouracil and leucovorin for the treatment of colorectal cancer. Cancer 1989; 63 Suppl. 6: 1036–44
Poon MA, O’Connell MJ, Moertel CG, et al. Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989; 7(10): 1407–18
Doroshow JH, Multhauf P, Leong L, et al. Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol 1990; 8(3): 491–501
Lockshin A, Danenberg PV. Biochemical factors affecting the tightness of 5-fluorodeoxyuridylate binding to human thymidylate synthetase. Biochem Pharmacol 1981; 30(3): 247–57
Cohen SS, Flaks JG, Barser HD, et al. The mode of action of 5-fluorouracil and its derivates. Proc Natl Acad Sci USA 1958; 44: 1004–12
Zittoun J. Pharmacokinetics and in vitro studies of 1-leucovorin. Comparison with the d and d,1-leucovorin. Ann Oncol 1993; 4 Suppl. 2: 1–5
Machover D, Goldschmidt E, Chollet P, et al. Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol 1986; 4(5): 685–96
Straw JA, Newman EM, Doroshow JH. Pharmacokinetics of leucovorin (D,L-5-formyltetrahydrofolate) after intravenous injection and constant intravenous infusion. NCI Monogr 1987; 5: 41–5 (NIH Publication No. 87-2901)
Voeller DM, Allegra CJ. Intracellular metabolism of 5-methyltetrahydrofolate and 5-formyltetrahydrofolate in a human breast-cancer line. Cancer Chemother Pharmacol 1994; 34(6): 491–6
Evans RM, Laskin JD, Hakala MT. Effect of excess folates and deoxinosine on the activity and site of action of 5-fluorouracil. Cancer Res 1981; 41(9): 3288–95
Keyomarsi K, Moran RG. Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells. Cancer Res 1986; 46(10): 5229–35
Chang Y-M, Bertino JR. Enhancement of fluoropyrimidine inhibition of cell growth by leucovorin and deoxynucleosides in a human squamous cell carcinoma cell line. Cancer Invest 1989; 7(6): 557–63
Moran RG, Scanion KL. Schedule-dependent enhancement of cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folic acid. Cancer Res 1991; 51(17): 4618–23
Drake JC, Voeller DM, Allegra CJ, et al. The effect of dose and interval between 5-fluorouracil and leucovorin on the formation of thymidylate synthase ternary complex in human cancer cells. Br J Cancer 1995; 71(6): 1145–50
Newman EM, Akman SA, Harrison JS, et al. Pharmacokinetics and toxicity of continuous infusion (6S)-folinic acid and bolus 5-fluorouracil in patients with advanced cancer. Cancer Res 1992; 52(9): 2408–12
Schilsky RL, Ratain MJ. Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration. J Natl Cancer Inst 1990; 82(17): 1411–5
Gibaldi M, Perrier D, editors. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, 1982
Machover D, Grison X, Goldschmidt E, et al. Flourouracil combined with pure (6S)-stereoisomer of folinic acid in high doses for treatment of patients with advanced colorectal carcinoma: a phase I-II study. J Natl Cancer Inst 1992; 84(5): 321–7
Nixon PF, Bertino JR. Effective absorption and utilization of oral formyltetrahydrofolate in man. N Engl J Med 1972; 286(4): 175–9
Whitehead VM, Pratt R, Viallet A, et al. Intestinal conversion of folinic acid to 5-methyltetrahydrofolate in man. Br J Haematol 1972; 22(1): 63–72
Mini E, Mazzei T, Coronnello M, et al. Effects of 5-methyltetrahydrofolate on the activity of fluoropyrimidines against human leukemia (CCRF-CEM) cells. Biochem Pharmacol 1987; 36(18): 2905–11
Houghton JA, Williams LG, de Graaf SSN, et al. Comparison of the conversion of 5-formyltetrahydrofolate and 5-methyltetrahydrofolate to 5,10-methylenetetrahydrofolates and tetrahydrofolates in human colon tumors. Cancer Comm 1989; 1(3): 167–74
Hougton JA, Williams LG, de Graaf SSN, et al. Relationship between dose rate of [6R,S]leucovorin administration, plasma concentrations of reduced folates, and pools of 5,10-methylene-tetrahydrofolates and tetrahydrofolates in human colon adenocarcinoma xenografts. Cancer Res 1990; 50(12): 3493–502
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Vannozzi, M.O., Nobile, M.T., Sanguineti, O. et al. Pharmacokinetics of (6S)-Leucovorin and 5-Methyltetrahydrofolate after 4-Hour Continuous Intravenous Infusion Followed by Repeated Oral Doses of (6S)-Leucovorin in Patients with Colorectal Cancer Treated with 5-Fluorouracil. Clin. Drug Invest. 12, 39–45 (1996). https://doi.org/10.2165/00044011-199612010-00005
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DOI: https://doi.org/10.2165/00044011-199612010-00005