Skip to main content
SpringerLink
Log in

Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit

  • Original Articles
  • Doxorubicin, Infusion/Bolus, Doxorubicinol, Pharmacokinetics
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Cumulative dose-related, chronic cardiotoxicity is a serious clinical complication of anthracycline therapy. Clinical and animal studies have demonstrated that continuous infusion, compared to bolus injection of doxorubicin, decreases the risk of cardiotoxicity. Continuous infusion of doxorubicin may result in decreased cardiac tissue concentrations of anthracyclines, including the primary metabolite doxorubicinol, which may also be an important contributor to cardiotoxicity. In this study, doxorubicin and doxorubicinol plasma pharmacokinetics and tissue concentrations were compared in New Zealand white rabbits following intravenous administration of doxorubicin (5 mg·kg−1) by bolus and continuous infusion. Blood samples were obtained over a 72-h period after doxorubicin administration to determine plasma doxorubicin and doxorubicinol concentrations. Rabbits were killed 7 days after the completion of doxorubicin administration and tissue concentrations of doxorubicin and doxorubicinol in heart, kidney, liver, and skeletal muscle were measured. In further experiments, rabbits were killed 1 h after bolus injection of doxorubicin and at the completion of a 24-h doxorubicin infusion (anticipated times of maximum heart anthracycline concentrations) to compare cardiac concentrations of doxorubicin and doxorubicinol following both methods of administration. Peak plasma concentrations of doxorubicin (1739±265 vs 100±10 ng·ml−1) and doxorubicinol (78±3 vs 16±3 ng·ml−1) were significantly higher following bolus than infusion dosing. In addition, elimination half-life of doxorubicinol was increased following infusion. However, other plasma pharmacokinetic parameters for doxorubicin and doxorubicinol, including AUC∞, were similar following both methods of doxorubicin administration. Peak left ventricular tissue concentrations of doxorubicin (16.92±0.9 vs 3.59±0.72 μg·g−1 tissue;P<0.001) and doxorubicinol (0.24±0.02 vs 0.09±0.01 μg·g−1 tissue;P<0.01) following bolus injection of doxorubicin were significantly higher than those following infusion administration. Tissue concentrations of parent drug and metabolite in bolus and infusion groups were similar 7 days after dosing. The results suggest that cardioprotection following doxorubicin infusion may be related to attenuation of the peak plasma or cardiac concentrations of doxorubicin and/or doxorubicinol.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Arcamone F (1976) Synthesis and antitumor activity of 4-demethoxydaunorubicin, 4′-demethoxy-7,9-diepidaunorubicin, and other beta anomers. Cancer Treat Rep 60: 829

    Google Scholar 

  2. Bachur NR, Gee M (1971) Daunorubicin metabolism by rat tissue preparations. J Pharmacol Exp Ther 177: 567

    Google Scholar 

  3. Boucek RJ, Olson RD, Brenner DE, Ogunbunmi EM, Inui M, Fleischer S (1987) The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. J Biol Chem 262: 15851

    Google Scholar 

  4. Brenner DE, Grosh WW, Wilkinson GER, Cooper J, Noone R, Stein R, Greco FA, Hande KR (1983) Clinical pharmacology of adriamycin (A) administered by continuous infusion: comparison to bolus administration. Proc Am Assoc Cancer Res 27: 134

    Google Scholar 

  5. Brenner DE, Noone R, Hande KR (1984) The rabbit as an in vivo model of anthracyline pharmacology: comparison of doxorubicin (dox) pharmacology in the rabbit (rab) and human (hum). Proc Am Assoc Cancer Res 28: 300

    Google Scholar 

  6. Bristow MR, Mason JW, Billingham ME, Daniels JR (1978) Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 88: 168

    Google Scholar 

  7. Carlson WR, Sikic BI (1983) Continuous infusion or bolus injection in cancer chemotherapy. Ann Intern Med 99: 823

    Google Scholar 

  8. Cheblowski RT, Paroly WS, Pugh RP, Hueser J, Jacobs EM, Pajak TF, Bateman JP (1980) Adriamycin given as a weekly schedule without loading dose; clinically effective with reduced incidence of cardiotoxicity. Cancer Treat Rep 64: 47

    Google Scholar 

  9. Colombo T, Donelli MG, Urso R, Dallarda S, Bartosek I, Guitani A (1989) Doxorubicin toxicity and pharmacokinetics in old and young rats. Exp Gerontol 24: 159

    Google Scholar 

  10. Cusack BJ, Tesnohlidek DA, Loseke VL, Vestal RE, Brenner DE, Olson RD (1988) Effect of phenytoin on the pharmacokinetics of doxorubicin and doxorubicinol in the rabbit. Cancer Chemother Pharmacol 22: 294

    Google Scholar 

  11. Cusack BJ, Young SP, Loseke VL, Hurty MR, Olson RD (1992) Effect of low-protein diet on doxorubicin pharmacokinetics in the rabbit. Cancer Chemother Pharmacol 30: 145

    Google Scholar 

  12. Danesi R, Paperelli A, Bernardini N, Del Tacea M (1988) Cytofluorescence localization and disposition of doxorubicin and doxorubicinol in rat cardiac tissue. Eur J Cancer Clin Oncol 24: 1123

    Google Scholar 

  13. Del Tacea M, Danesi R, Ducci M, Bernardini C, Romanini A (1985) Might adriamycinol contribute to adriamycin-induced cardiotoxicity? Pharmacol Res Commun 17: 1073

    Google Scholar 

  14. Eksborg S, Strandler H-S, Edsmyr F, Naslund I, Tahvanainen P (1985) Pharmacokinetics study of IV infusions of adriamycin. Eur J Clin Pharmacol 28: 205

    Google Scholar 

  15. Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker, New York

    Google Scholar 

  16. Hortobagyi GN, Frye D, Buzdar AU, Ewer MS, Ewer MS, Fraschini G, Hug V, Ames F, Montague E, Carrasco CH, Mackay B, Benjamin RS (1989) Decreased cardiac toxicity of doxorubicin administered by continunous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63: 37

    Google Scholar 

  17. Ito H, Miller SC, Billingham ME, Akimoto H, Torti SV, Wade R, Gahlmann R, Lyons G, Kedes L, Torti FM (1990) Doxorubicin selectively inhibits muscle gene expression in cardiac muscle in vivo and in vitro. Proc Natl Acad Sci USA 87: 4275

    Google Scholar 

  18. Jain KK, Casper ES, Geller NL, Hakes TB, Kaufmann RJ, Currie V, Schwartz W, Cassidy C, Petroni GR, Young CW, Wittes RE (1985) A prospective randomized comparison of epirubicin and doxorubicin in patients with advanced breast cancer. J Clin Oncol 3: 818

    Google Scholar 

  19. Legha SS, Benjamin RS, Mackay B, Ewer M, Wallace S, Valdivieso M, Rasmussen SL, Blumenschein SR, Freirich EJ (1982) Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96: 133

    Google Scholar 

  20. Legha SS, Benjamin RS, Mackay B, Yap HY, Wallace S, Ewer M, Blumenschein GR, Freirich EJ (1982) Adriamycin therapy by continuous infusion in patients with metastatic breast cancer. Cancer 49: 1762

    Google Scholar 

  21. Olson RD, Mushlin PS (1990) Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 4: 3076

    Google Scholar 

  22. Olson RD, Mushlin MS, Brenner DE, Fleischer S, Cusack BJ, Chang BK, Boucek RJ Jr (1988) Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci USA 85: 3585

    Google Scholar 

  23. Pacciarini MA, Barbieri B, Colombo T, Broggini M, Garattini AS, Donelli MG (1978) Distribution and antitumor activity of adriamycin given in high-dose and a repeat low-dose schedule to mice. Cancer Treat Rep 62: 791

    Google Scholar 

  24. Papoian T, Lewis W (1991) Selective alterations in rat cardiac mRNA induced by doxorobicin: possible subcellular mechanisms. Exp Mol Pathol 54: 112

    Google Scholar 

  25. Rahman A, White G, More N, Schein PS (1985) Pharmacological, toxicological, and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes. Cancer Res 45: 796

    Google Scholar 

  26. Shapira J, Gotfried M, Lishner M, Ravid M (1990) Reduced cardiotoxicity of doxorubicin by a 6-hour infusion regimen. A prospective randomized evaluation. Cancer 65: 870

    Google Scholar 

  27. Solcia E, Ballerini L, Bellini O et al. (1981) Cardiomyopathy of doxorubicin in experimental animals: factors affecting the severity, distribution and evolution of myocardial lesions. Tumori 67: 461

    Google Scholar 

  28. Storm G, van Hoesel QGCM, Groot G de, Kop W, Steerenberg PA, Hillen FC (1989) A comparative study of the antitumor effect, cardiotoxicity and nephrotoxicity of doxorubicin given as bolus, continuous infusion or entrapped liposomes in the Lou/M rat. Cancer Chemother Pharmacol 24: 341

    Google Scholar 

  29. Takanashi S, Bachur NR (1976) Adriamycin metabolism in man; evidence from urinary metabolites. Drug Metab Dispos 4: 79

    Google Scholar 

  30. Terasaki T, Iga T, Sugiyama Y, Sawada Y, Manubu H (1984) Nuclear binding as a determinant of tissue distribution of adriamycin, daunomycin, adriamycinol, daunorubicinol and actinomycin D. J Pharmacobiodyn 7: 269

    Google Scholar 

  31. Torti FM, Bristow MR, Howes AE, Aston D, Stockdale FE, Carter SK, Kohler M, Brown BW, Billingham ME (1983) Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule. Assessment by endomyocardial biopsy. Ann Intern Med 99: 745

    Google Scholar 

  32. Twelves CJ, Dobbs NA, Aldhous M, Harper PG, Rubens RD, Richards MA (1991) Comparative pharmacokinetics of doxorubicin given by three different schedules with equal dose intensity in patients with breast cancer. Cancer Chemother Pharmacol 28: 302

    Google Scholar 

  33. Umsawadi T, Valdievieso M, Booser DJ, Barkley HT, Ewer M, MacKay B, Dhingra HM, Murphy WK, Spitzer G, Chiuten DF, Dixon C, Farha P, Carr DT (1989) Weekly doxorubicin versus doxorubicin every 3 weeks in cyclophosphamide, doxorubicin, and cisplatin chemotherapy for non-small cell cancer. Cancer 64: 1995

    Google Scholar 

  34. Van Hoesel QGCM, Steerenberg PA, Cromellin DJA, van Dijk A, Oort W van, Klein S, Douze JMC, Wildt DJ de, Hillen FC (1984) Reduced cardiotoxicity and nephrotoxicity with preservation of antitumor activity of doxorubicin entrapped in stable liposomes in the LOU/M Wsl rat. Cancer Res 44: 3698

    Google Scholar 

  35. Von Hoff DD, Rozencweig M, Layard M, Slavik M, Muggia FM (1977) Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am J Med 62: 1977

    Google Scholar 

  36. Weiss AJ, Manthel RW (1977) Experience with the use of adriamycin in combination with other anticancer agents using a weekly schedule, with particular reference to lack of cardiac toxicity. Cancer 40: 2046

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Gerontology and Clinical Pharmacology Research Unit, VA Medical Center (111), 500 W. Fort St., 83702-4598, Boise, ID, USA

    Barry J. Cusack, Stephan P. Young, Joni Driskell & Richard D. Olson

  2. School of Medicine, University of Washington, Seattle, Washington, USA

    Barry J. Cusack & Richard D. Olson

Authors
  1. Barry J. Cusack
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stephan P. Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joni Driskell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard D. Olson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cusack, B.J., Young, S.P., Driskell, J. et al. Doxorubicin and doxorubicinol pharmacokinetics and tissue concentrations following bolus injection and continuous infusion of doxorubicin in the rabbit. Cancer Chemother. Pharmacol. 32, 53–58 (1993). https://doi.org/10.1007/BF00685876

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00685876

Keywords

Search

Navigation