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.
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Arcamone F (1976) Synthesis and antitumor activity of 4-demethoxydaunorubicin, 4′-demethoxy-7,9-diepidaunorubicin, and other beta anomers. Cancer Treat Rep 60: 829
Bachur NR, Gee M (1971) Daunorubicin metabolism by rat tissue preparations. J Pharmacol Exp Ther 177: 567
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
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
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
Bristow MR, Mason JW, Billingham ME, Daniels JR (1978) Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med 88: 168
Carlson WR, Sikic BI (1983) Continuous infusion or bolus injection in cancer chemotherapy. Ann Intern Med 99: 823
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
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
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
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
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
Del Tacea M, Danesi R, Ducci M, Bernardini C, Romanini A (1985) Might adriamycinol contribute to adriamycin-induced cardiotoxicity? Pharmacol Res Commun 17: 1073
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
Gibaldi M, Perrier D (1982) Pharmacokinetics, 2nd edn. Dekker, New York
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
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
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
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
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
Olson RD, Mushlin PS (1990) Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 4: 3076
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
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
Papoian T, Lewis W (1991) Selective alterations in rat cardiac mRNA induced by doxorobicin: possible subcellular mechanisms. Exp Mol Pathol 54: 112
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
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
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
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
Takanashi S, Bachur NR (1976) Adriamycin metabolism in man; evidence from urinary metabolites. Drug Metab Dispos 4: 79
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
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
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
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
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
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
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
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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
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DOI: https://doi.org/10.1007/BF00685876