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. 1989 Sep;28(3):289–295. doi: 10.1111/j.1365-2125.1989.tb05429.x

Pharmacokinetics of (-)-folinic acid after oral and intravenous administration of the racemate.

P O Greiner 1, J Zittoun 1, J Marquet 1, J M Cheron 1
PMCID: PMC1379947  PMID: 2789922

Abstract

1. A pharmacokinetic study of the natural (-)-isomer of folinic acid ((-)-5 CHOTHF) and of total (-)-folates was performed in 12 healthy subjects after i.v. and oral administration of the racemic form of folinic acid. 2. After a 25 mg i.v. injection, (-)-5 CHOTHF kinetics were described by a biexponential function. The mean steady state volume of distribution (Vss) was 161; systemic and renal clearances averaged 335 and 53 ml min-1, respectively. After the same oral dose, (-)-5 CHOTHF was rapidly absorbed. Plasma concentrations of unchanged drug were much lower than those achieved after i.v. administration but in nine subjects, the disposition kinetics were also biexponential. Absolute bioavailability was only 4% as a consequence of a significant intestinal first pass effect. 3. AUC and t1/2Z values for total (-)-folates were similar after both routes of administration, indicating that the drug was fully absorbed. However the AUC of the active metabolite after i.v. dosage was only half that after oral dosage. 4. The amounts of total (-)-folates excreted in urine after both routes of administration were not significantly different and averaged one third of the dose after 24 h, whereas excretion of (-)-5 CHOTHF was three times less after oral treatment than after parenteral treatment. 5. Oral administration is a more suitable route for folinic acid therapy because more of the active metabolite is produced than after parenteral injection.

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Selected References

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  1. Bender J. F., Grove W. R., Fortner C. L. High-dose methotrexate with folinic acid rescue. Am J Hosp Pharm. 1977 Sep;34(9):961–965. [PubMed] [Google Scholar]
  2. Coiffier B., Bryon P. A., Berger F., Archimbaud E., Ffrench M., Extra J. M., Guyotat D., Fiere D., Gentilhomme O., Magaud J. P. Intensive and sequential combination chemotherapy for aggressive malignant lymphomas (protocol LNH-80). J Clin Oncol. 1986 Feb;4(2):147–153. doi: 10.1200/JCO.1986.4.2.147. [DOI] [PubMed] [Google Scholar]
  3. Decker D. A., Edmonson J. H., Gilchrist G. S., Kovach J. S., Offord J. R., Taylor W. F. High-dose methotrexate with a safe rescue program. Oncology. 1981;38(5):262–264. doi: 10.1159/000225566. [DOI] [PubMed] [Google Scholar]
  4. Frei E., 3rd, Blum R. H., Pitman S. W., Kirkwood J. M., Henderson I. C., Skarin A. T., Mayer R. J., Bast R. C., Garnick M. B., Parker L. M. High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity. Am J Med. 1980 Mar;68(3):370–376. doi: 10.1016/0002-9343(80)90105-9. [DOI] [PubMed] [Google Scholar]
  5. GROSSOWICZ N., MANDELBAUM-SHAVIT F., DAVIDOFF R., ARONOVITCH J. Microbiologic determination of folic acid derivatives in blood. Blood. 1962 Nov;20:609–616. [PubMed] [Google Scholar]
  6. Gomeni C., Gomeni R. IGPHARM: interactive graphic package for pharmacokinetic analysis. Comput Biomed Res. 1978 Aug;11(4):345–361. doi: 10.1016/0010-4809(78)90017-4. [DOI] [PubMed] [Google Scholar]
  7. Guelen P. J., Vree T. B., de Vos D., Lamers K. Comparative bioavailability and kinetics of folinic acid in the pharmaceutical formulations of Rescuvolin and Ledervorin in healthy volunteers. Biopharm Drug Dispos. 1988 Jan-Feb;9(1):31–39. doi: 10.1002/bod.2510090105. [DOI] [PubMed] [Google Scholar]
  8. HERBERT V., BAKER H., FRANK O., PASHER I., SOBOTKA H., WASSERMAN L. R. The measurement of folic acid activity in serum: a diagnostic aid in the differentiation of the megaloblastic anemias. Blood. 1960 Feb;15:228–235. [PubMed] [Google Scholar]
  9. Henderson I. C., Gelman R., Canellos G. P., Frei E., 3rd Prolonged disease-free survival in advanced breast cancer treated with "super-CMF" adriamycin: an alternating regimen employing high-dose methotrexate with citrovorum factor rescue. Cancer Treat Rep. 1981;65 (Suppl 1):67–75. [PubMed] [Google Scholar]
  10. Kirwan J. R., Narebor E. M. Absorption of large oral doses of 5-formyltetrahydrofolate in man. Br J Cancer. 1976 Dec;34(6):671–673. doi: 10.1038/bjc.1976.231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Machover D., Goldschmidt E., Chollet P., Metzger G., Zittoun J., Marquet J., Vandenbulcke J. M., Misset J. L., Schwarzenberg L., Fourtillan J. B. Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high-dose folinic acid. J Clin Oncol. 1986 May;4(5):685–696. doi: 10.1200/JCO.1986.4.5.685. [DOI] [PubMed] [Google Scholar]
  12. Mehta B. M., Gisolfi A. L., Hutchison D. J., Nirenberg A., Kellick M. G., Rosen G. Serum distribution of citrovorum factor and 5-methyltetrahydrofolate following oral and im administration of calcium leucovorin in normal adults. Cancer Treat Rep. 1978 Mar;62(3):345–350. [PubMed] [Google Scholar]
  13. Nixon P. F., Bertino J. R. Effective absorption and utilization of oral formyltetrahydrofolate in man. N Engl J Med. 1972 Jan 27;286(4):175–179. doi: 10.1056/NEJM197201272860402. [DOI] [PubMed] [Google Scholar]
  14. Pinkerton C. R. Is folate absorption impaired by high dose methotrexate? Br J Cancer. 1983 Feb;47(2):303–305. doi: 10.1038/bjc.1983.40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Skarin A. T., Zuckerman K. S., Pitman S. W., Rosenthal D. S., Moloney W., Frei E., 3rd, Canellos G. P. High-dose methotrexate with folinic acid in the treatment of advanced non-Hodgkin lymphoma including CNS involvement. Blood. 1977 Dec;50(6):1039–1047. [PubMed] [Google Scholar]
  16. Stoller R. G., Kaplan H. G., Cummings F. J., Calabresi P. A clinical and pharmacological study of high-dose methotrexate with minimal leucovorin rescue. Cancer Res. 1979 Mar;39(3):908–912. [PubMed] [Google Scholar]
  17. Straw J. A., Newman E. M., Doroshow J. H. Pharmacokinetics of leucovorin (D,L-5-formyltetrahydrofolate) after intravenous injection and constant intravenous infusion. NCI Monogr. 1987;(5):41–45. [PubMed] [Google Scholar]
  18. Straw J. A., Szapary D., Wynn W. T. Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects. Cancer Res. 1984 Jul;44(7):3114–3119. [PubMed] [Google Scholar]
  19. Taguchi H. The metabolism of folinic acid (leucovorin) following oral and parenteral administration. J Nutr Sci Vitaminol (Tokyo) 1981;27(4):283–290. doi: 10.3177/jnsv.27.283. [DOI] [PubMed] [Google Scholar]
  20. WATERS A. H., MOLLIN D. L. Studies on the folic acid activity of human serum. J Clin Pathol. 1961 Jul;14:335–344. doi: 10.1136/jcp.14.4.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Whitehead V. M., Pratt R., Viallet A., Cooper B. A. Intestinal conversion of folinic acid to 5-methyltetrahydrofolate in man. Br J Haematol. 1972 Jan;22(1):63–72. doi: 10.1111/j.1365-2141.1972.tb08787.x. [DOI] [PubMed] [Google Scholar]
  22. Yin M. B., Zakrzewski S. F., Hakala M. T. Relationship of cellular folate cofactor pools to the activity of 5-fluorouracil. Mol Pharmacol. 1983 Jan;23(1):190–197. [PubMed] [Google Scholar]

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