Summary
The clinical pharmacology of 4-demethoxydaunorubicin (4-DMDNR) was studied in 28 patients with advanced breast cancer, using a sensitive reverse-phase HPLC technique. All patients had normal renal and hepatic function. The serum levels of 4-DMDNR after a single i.v. bolus injection followed a triple exponential decay curve (T1/2α=9.6 min, T1/2β=3.2 h and T1/2γ=34.7 h) and conformed to a three-compartment model. Comparison of the area under the curve (AUC) and urinary excretion for the oral and i.v routes suggests an oral bioavailability of approximately 24%. In patients treated with a schedule of weekly oral administration for periods of up to 12 months there was no significant alteration in either AUC or elimination half-life for the parent drug or its principal metabolite 13-OH4DMDNR. Moreover, there was no evidence of accumulation of the metabolite although measurable amounts were present 7 days after administration of 4-DMDNR.
Similar content being viewed by others
References
Arcamone F, Bernardi L, Giardino P, Patelli P, Di Marco A, Casazza AM, Pratesi G, Reggiani P (1976) Synthesis and antitumour activity of 4-demethoxydaunorubicin, 4-demethoxy7,9-diepidaunorubicin, and their B anomers. Cancer Treat Rep 60: 829
Berman E, Wittes RE, Leyland-Jones B, Casper ES, Gralla RJ, Howard J, Williams L, Baratz R, Young CW (1983) Phase I and clinical pharmacology studies of intravenous and oral administration of 4-demethoxydaunorubicin in patients with advanced cancer. Cancer Res 43:6096
Bonfante V, Ferarri L, Villani F, Bonnadonna G (1983) Phase I study of 4-demethoxydaunorubicin. Investigational New Drugs 1: 161
Box MJ, Davies D, Swann WH (1969) Non-linear optimization techniques. Oliver and Boyd, Edinburgh. p 22 (ICI monograph no 5)
Casazza AM, Barbieri B, Fumagalli A, Geroni MC (1983) Biologic activity of 4-demethoxy-13-dihydrodaunorubicin. Proc Am Assoc Cancer Res 24:251
Daghestani AN, Zalmen AA, Leyland-Jones B, Gee TS, Kempin SJ, Mertelsmann R, Budman D, Schulman P, Baratz R, Williams L, Clarkson BD, Young CW (1985) Phase I and II clinical and pharmacological study of 4-demethoxydaunorubicin (4-DMDNR) in adult patients with acute leukemia. Cancer Res 45: 1408
Di Marco A, Casazza AM, Pratesi G (1977) Antitumour activity of 4-demethoxydaunorubicin administered orally. Cancer Treat Rep 61:893
Gause GF, Brazhnikova MG, Shorin VA (1974) A new antitumour antibiotic, carminomycin (NSC-180024). Cancer Chemother Rep 58: 255
Gil P, Favre R, Durand A, Iliadis A, Cano JP, Carcassonne Y (1983) Time dependency of adriamycin and adriamycinol kinetics. Cancer Chemother Pharmacol 10:120
Israel M, Pegg WJ, Wilkinson PM, Garnick MB (1978) Liquid chromatographic analysis of adriamycin and metabolites in biological fluids. J Liquid Chromatogr 1:795
Kaplan S, Martini A, Varini M, Togni P, Cavalli F (1982) Phase I trial of 4-demethoxydaunorubicin with single i.v. doses. Eur J Cancer 18: 1303
Kaplan S, Sessa C, Willems Y, Pacciarini MA, Tamassia V, Cavalli F (1984) Phase I trial of 4-demthoxydaunorubicin (4-DMDNR) with single oral doses. Investigational New Drugs 2 281
Karnofsky DA, Burchenal JH (1949) The clinical evaluation of chemotherapeutic agents in cancer: In: Macleod CM (ed) Evaluation of chemotherapeutic agents. Columbia University Press, New York, p 191
Robert J, Hoerni B, Virgnaud P, Lagarde C (1983) Early-phase pharmacolinetics of doxorubicin in non-Hodgkin lymphoma patients. Cancer Chemother Pharmacol 10: 115
Vrignaud P, Egdbali H, Hoerni B, Iliadis A, Robert J (1985) Pharmacokinetics and metabolism of epirubicin during repetitive courses of adriamycin in Hodgkin's patients. Eur J Cancer 21: 107
Young RC, Ozols RF, Myers CE (1981) The anthracycline antineoplastic drugs. N Engl J Med 305: 139
Author information
Authors and Affiliations
Additional information
This work was supported by the Cancer Research Campaign and Farmitalia Carlo Erba Ltd
Rights and permissions
About this article
Cite this article
Smith, D.B., Margison, J.M., Lucas, S.B. et al. Clinical pharmacology of oral and intravenous 4-demethoxydaunorubicin. Cancer Chemother. Pharmacol. 19, 138–142 (1987). https://doi.org/10.1007/BF00254566
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00254566