Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1994 Aug;70(2):324–329. doi: 10.1038/bjc.1994.301

Daunorubicin pharmacokinetics and the correlation with P-glycoprotein and response in patients with acute leukaemia.

P Galettis 1, J Boutagy 1, D D Ma 1
PMCID: PMC2033508  PMID: 7914424

Abstract

The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies.

Full text

PDF
324

Selected References

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

  1. Alberts D. S., Bachur N. R., Holtzman J. L. The pharmacokinetics of daunomycin in man. Clin Pharmacol Ther. 1971 Jan-Feb;12(1):96–104. doi: 10.1002/cpt197112196. [DOI] [PubMed] [Google Scholar]
  2. Bradley G., Juranka P. F., Ling V. Mechanism of multidrug resistance. Biochim Biophys Acta. 1988 Aug 3;948(1):87–128. doi: 10.1016/0304-419x(88)90006-6. [DOI] [PubMed] [Google Scholar]
  3. Campos L., Guyotat D., Archimbaud E., Calmard-Oriol P., Tsuruo T., Troncy J., Treille D., Fiere D. Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood. 1992 Jan 15;79(2):473–476. [PubMed] [Google Scholar]
  4. Chan H. S., Haddad G., Thorner P. S., DeBoer G., Lin Y. P., Ondrusek N., Yeger H., Ling V. P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N Engl J Med. 1991 Dec 5;325(23):1608–1614. doi: 10.1056/NEJM199112053252304. [DOI] [PubMed] [Google Scholar]
  5. Fojo A., Akiyama S., Gottesman M. M., Pastan I. Reduced drug accumulation in multiply drug-resistant human KB carcinoma cell lines. Cancer Res. 1985 Jul;45(7):3002–3007. [PubMed] [Google Scholar]
  6. Holmes J., Jacobs A., Carter G., Janowska-Wieczorek A., Padua R. A. Multidrug resistance in haemopoietic cell lines, myelodysplastic syndromes and acute myeloblastic leukaemia. Br J Haematol. 1989 May;72(1):40–44. doi: 10.1111/j.1365-2141.1989.tb07649.x. [DOI] [PubMed] [Google Scholar]
  7. Huffman D. H., Bachur N. R. Daunorubicin metabolism in acute myelocytic leukemia. Blood. 1972 May;39(5):637–643. [PubMed] [Google Scholar]
  8. Kartner N., Ling V. Multidrug resistance in cancer. Sci Am. 1989 Mar;260(3):44–51. doi: 10.1038/scientificamerican0389-44. [DOI] [PubMed] [Google Scholar]
  9. Kartner N., Shales M., Riordan J. R., Ling V. Daunorubicin-resistant Chinese hamster ovary cells expressing multidrug resistance and a cell-surface P-glycoprotein. Cancer Res. 1983 Sep;43(9):4413–4419. [PubMed] [Google Scholar]
  10. Kokenberg E., Sonneveld P., Sizoo W., Hagenbeek A., Löwenberg B. Cellular pharmacokinetics of daunorubicin: relationships with the response to treatment in patients with acute myeloid leukemia. J Clin Oncol. 1988 May;6(5):802–812. doi: 10.1200/JCO.1988.6.5.802. [DOI] [PubMed] [Google Scholar]
  11. Krishnamachary N., Center M. S. The MRP gene associated with a non-P-glycoprotein multidrug resistance encodes a 190-kDa membrane bound glycoprotein. Cancer Res. 1993 Aug 15;53(16):3658–3661. [PubMed] [Google Scholar]
  12. Ma D. D., Scurr R. D., Davey R. A., Mackertich S. M., Harman D. H., Dowden G., Isbister J. P., Bell D. R. Detection of a multidrug resistant phenotype in acute non-lymphoblastic leukaemia. Lancet. 1987 Jan 17;1(8525):135–137. doi: 10.1016/s0140-6736(87)91969-6. [DOI] [PubMed] [Google Scholar]
  13. Marie J. P., Faussat-Suberville A. M., Zhou D., Zittoun R. Daunorubicin uptake by leukemic cells: correlations with treatment outcome and mdr1 expression. Leukemia. 1993 Jun;7(6):825–831. [PubMed] [Google Scholar]
  14. Marie J. P., Zittoun R., Sikic B. I. Multidrug resistance (mdr1) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood. 1991 Aug 1;78(3):586–592. [PubMed] [Google Scholar]
  15. Marsh W., Sicheri D., Center M. S. Isolation and characterization of adriamycin-resistant HL-60 cells which are not defective in the initial intracellular accumulation of drug. Cancer Res. 1986 Aug;46(8):4053–4057. [PubMed] [Google Scholar]
  16. Pastan I., Gottesman M. Multiple-drug resistance in human cancer. N Engl J Med. 1987 May 28;316(22):1388–1393. doi: 10.1056/NEJM198705283162207. [DOI] [PubMed] [Google Scholar]
  17. Paul C., Liliemark J., Tidefelt U., Gahrton G., Peterson C. Pharmacokinetics of daunorubicin and doxorubicin in plasma and leukemic cells from patients with acute nonlymphoblastic leukemia. Ther Drug Monit. 1989;11(2):140–148. doi: 10.1097/00007691-198903000-00004. [DOI] [PubMed] [Google Scholar]
  18. Pirker R., Wallner J., Geissler K., Linkesch W., Haas O. A., Bettelheim P., Hopfner M., Scherrer R., Valent P., Havelec L. MDR1 gene expression and treatment outcome in acute myeloid leukemia. J Natl Cancer Inst. 1991 May 15;83(10):708–712. doi: 10.1093/jnci/83.10.708. [DOI] [PubMed] [Google Scholar]
  19. Rothenberg M. L., Mickley L. A., Cole D. E., Balis F. M., Tsuruo T., Poplack D. G., Fojo A. T. Expression of the mdr-1/P-170 gene in patients with acute lymphoblastic leukemia. Blood. 1989 Sep;74(4):1388–1395. [PubMed] [Google Scholar]
  20. Speth P. A., Linssen P. C., Boezeman J. B., Wessels H. M., Haanen C. Leukemic cell and plasma daunomycin concentrations after bolus injection and 72 h infusion. Cancer Chemother Pharmacol. 1987;20(4):311–315. doi: 10.1007/BF00262582. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES