Skip to main content
NCBI home page
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1979 Sep;8(3):219–227. doi: 10.1111/j.1365-2125.1979.tb01005.x

Pharmacokinetics of cytosine arabinoside in patients with acute myeloid leukaemia.

A L Harris, C Potter, C Bunch, J Boutagy, D J Harvey, D G Grahame-Smith
PMCID: PMC1429786  PMID: 291436

Abstract

1 The pharmacokinetics of cytosine arabinoside were studied after a single i.v. bolus of 2 mg/kg ara-C in patients with newly diagnosed untreated AML, using a bioassay and GC-MS method to measure the plasma concentrations. 2 Most patients showed a bi- or tri-phasic decline in plasma concentrations with time. Plasma clearance was 3.9 to 18.1 l/min as measured by the GC-MS method, and terminal half-lives varied from 7--107 min. 3 There was poor correlation of the GC-MS assay with the bioassay, probably because the latter was interfered with by the release of endogenous nucleosides from blasts after after ara-C. 4 Plasma concentrations were measured by GC-MS during continuous infusions in 14 patients. Plasma clearances were much lower than after a bolus, 0.39 to 5.25 l/min. 5 There was no correlation of response (remission or fall in peripheral blast count) with exposure to ara-C calculated from infusion dose, clearance and duration of infusion. 6 This study shows that ara-C pharmacokinetics varies markedly from patient to patient and that there is a wide range in the plasma concentrations associated with therapeutic response.

Full text

PDF
219

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baguley B. C., Falkenhaug E. M. Plasma half-life of cytosine arabinoside (NSC-63878) in patients treated for acute myeloblastic leukemia. Cancer Chemother Rep. 1971 Jun;55(3):291–298. [PubMed] [Google Scholar]
  2. Bodey G. P., Coltman C. A., Hewlett J. S., Freireich E. J. Progress in the treatment of adults with acute leukemia: review of regimens containing cytarabine studied by the Southwest Oncology Group. Arch Intern Med. 1976 Dec;136(12):1383–1388. [PubMed] [Google Scholar]
  3. Boutagy J., Harvey D. J. Determination of cytosine arabinoside in human plasma by gas chromatography with a nitrogen-sensitive detector and by gas chromatography--mass spectrometry. J Chromatogr. 1978 Sep 1;146(2):283–296. doi: 10.1016/s0378-4347(00)81894-0. [DOI] [PubMed] [Google Scholar]
  4. CAESAR J., SHALDON S., CHIANDUSSI L., GUEVARA L., SHERLOCK S. The use of indocyanine green in the measurement of hepatic blood flow and as a test of hepatic function. Clin Sci. 1961 Aug;21:43–57. [PubMed] [Google Scholar]
  5. CULBERTSON J. W., WILKINS R. W., INGELFINGER F. J., BRADLEY S. E. The effect of the upright posture upon hepatic blood flow in normotensive and hypertensive subjects. J Clin Invest. 1951 Mar;30(3):305–311. doi: 10.1172/JCI102445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Camiener G. W. Studies of the enzymatic deamination of ara-cytidine. V. inhibition in vitro and in vivo by tetrahydrouridine and other reduced pyrimidine nucleosides. Biochem Pharmacol. 1968 Sep;17(9):1981–1991. doi: 10.1016/0006-2952(68)90114-7. [DOI] [PubMed] [Google Scholar]
  7. Camiener G. W. Studies of the enzymatic deamination of cytosine arabinoside. II. Properties of the deaminase of human liver. Biochem Pharmacol. 1967 Sep 9;16(9):1681–1689. doi: 10.1016/0006-2952(67)90243-2. [DOI] [PubMed] [Google Scholar]
  8. Chou T. C., Arlin Z., Clarkson B. D., Phillips F. S. Metabolism of 1-beta-D-arabinofuranosylcytosine in human leukemic cells. Cancer Res. 1977 Oct;37(10):3561–3570. [PubMed] [Google Scholar]
  9. Chu M. Y. Incorporation of arabinosyl cytosine into 2-7S ribonucleic acid and cell death. Biochem Pharmacol. 1971 Aug;20(8):2057–2063. doi: 10.1016/0006-2952(71)90406-0. [DOI] [PubMed] [Google Scholar]
  10. Chuang R. Y., Chuang L. F. Inhibition of RNA polymerase as a possible anti-leukaemic action of cytosine arabinoside. Nature. 1976 Apr 8;260(5551):549–550. doi: 10.1038/260549a0. [DOI] [PubMed] [Google Scholar]
  11. Finklestein J. Z., Scher J., Karon M. Pharmacologic studies of tritiated cytosine arabinoside (NSC-63878) in children. Cancer Chemother Rep. 1970 Feb;54(1):35–39. [PubMed] [Google Scholar]
  12. Furth J. J., Cohen S. S. Inhibition of mammalian DNA polymerase by the 5'-triphosphate of 1-beta-d-arabinofuranosylcytosine and the 5'-triphosphate of 9-beta-d-arabinofuranoxyladenine. Cancer Res. 1968 Oct;28(10):2061–2067. [PubMed] [Google Scholar]
  13. Gillette J. R. Factors affecting drug metabolism. Ann N Y Acad Sci. 1971 Jul 6;179:43–66. doi: 10.1111/j.1749-6632.1971.tb46890.x. [DOI] [PubMed] [Google Scholar]
  14. Graham F. L., Whitmore G. F. Studies in mouse L-cells on the incorporation of 1-beta-D-arabinofuranosylcytosine into DNA and on inhibition of DNA polymerase by 1-beta-D-arabinofuranosylcytosine 5'-triphosphate. Cancer Res. 1970 Nov;30(11):2636–2644. [PubMed] [Google Scholar]
  15. Greenberg P. L., VanKersen I., Mosny S. Cytotoxic effects of 1-beta-D-arabinofuranosylcytosine and 6-thioguanine in vitro on granulocytic progenitor cells. Cancer Res. 1976 Dec;36(12):4412–4417. [PubMed] [Google Scholar]
  16. Harris A. L., Grahame-Smith D. G. A study in the guinea-pig of the pharmacokinetics and pharmacodynamics of cytosine arabinoside [proceedings]. Br J Pharmacol. 1978 Mar;62(3):440P–441P. [PMC free article] [PubMed] [Google Scholar]
  17. Ho D. H. Distribution of kinase and deaminase of 1-beta-D-arabinofuranosylcytosine in tissues of man and mouse. Cancer Res. 1973 Nov;33(11):2816–2820. [PubMed] [Google Scholar]
  18. Ho D. H., Frei E., 3rd Clinical pharmacology of 1-beta-d-arabinofuranosyl cytosine. Clin Pharmacol Ther. 1971 Nov-Dec;12(6):944–954. doi: 10.1002/cpt1971126944. [DOI] [PubMed] [Google Scholar]
  19. Kessel D., Hall T. C., Rosenthal D. Uptake and phosphorylation of cytosine arabinoside by normal and leukemic human blood cells in vitro. Cancer Res. 1969 Feb;29(2):459–463. [PubMed] [Google Scholar]
  20. MAPLESON W. W. An electric analogue for uptake and exchange of inert gases and other agents. J Appl Physiol. 1963 Jan;18:197–204. doi: 10.1152/jappl.1963.18.1.197. [DOI] [PubMed] [Google Scholar]
  21. PETRAKIS N. L., MASOUREDIS S. P., MILLER P. The local blood flow in human bone marrow in leukemia and neoplastic diseases as determined by the clearance rate of radioiodide (I131). J Clin Invest. 1953 Oct;32(10):952–963. doi: 10.1172/JCI102821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Swartz R. D., Sidell F. R., Cucinell S. A. Effects of physical stress on the disposition of drugs eliminated by the liver in man. J Pharmacol Exp Ther. 1974 Jan;188(1):1–7. [PubMed] [Google Scholar]
  23. Wan S. H., Huffman D. H., Azarnoff D. L., Hoogstraten B., Larsen W. E. Pharmacokinetics of 1-beta-D-arabinofuranosylcytosine in humans. Cancer Res. 1974 Feb;34(2):392–397. [PubMed] [Google Scholar]
  24. Wilkinson G. R., Shand D. G. Commentary: a physiological approach to hepatic drug clearance. Clin Pharmacol Ther. 1975 Oct;18(4):377–390. doi: 10.1002/cpt1975184377. [DOI] [PubMed] [Google Scholar]
  25. van Prooijen R., van der Kleijn E., Haanen C. Pharmacokinetics of cytosine arabinoside in acute myeloid leukemia. Clin Pharmacol Ther. 1977 Jun;21(6):744–750. doi: 10.1002/cpt1977216744. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES