Summary
The metabolism and tissue distribution of aclacinomycin A (ACL), marcellomycin (MCM), and musettamycin (MST), three new anthracycline antibiotics, were compared after IV administration to mice. In plasma, total MCM- and ACL-derived fluorescence declined according to first-order kinetics, whereas an initial decline followed by a rebound was observed for MST. In plasma, MCM remained the predominant compound. ACL was eliminated more quickly, and was replaced by two metabolites, the reduced glycoside M1, and an aglycone. In the case of MST, two unidentified metabolites were observed in concentrations equivalent to that of the parent drug.
The three drugs were distributed widely to organs, but only ACL achieved measurable concentrations in the brain. Initially, high concentrations of all three drugs were present in the lungs, but these decreased quickly to values similar to those present in the liver and kidneys. Intermediate concentrations of the three drugs were measured in heart and skeletal muscle. Splenic concentrations of all three drugs rose progressively, reaching a maximum at 8 h after injection in the case of ACL and MST, and at 24 h after injection in the case of MCM. Concentrations of the metabolites of MCM and MST were low in all organs except liver and kidney, where the aglycones 7-deoxypyrromycinone and bisanhydropyrromycinone were seen. The metabolism of ACL was extensive. Aglycones were dominant in the liver and kidneys, whereas reduced glycosides predominated in the spleen. These observations indicate that the murine pharmacology of these three structurally similar drugs differs markedly.
Similar content being viewed by others
References
Andrews PA, Brenner DE, Chou FE, Kubo H, Bachur NR (1980) Facile and definitive determination of human Adriamycin and daunorubicin metabolites by high-pressure liquid chromatography. Drug Metab Dispos 8: 152
Benjamin RS, Riggs CE, Jr, Bachur NR (1977) Plasma pharmacokinetics of Adriamycin and its metabolites in humans with normal hepatic and renal function. Cancer Res 37: 1417
Casper ES, Gralla RS, Young CW (1981) Clinical phase I study of aclacinomycin A by an evaluation of an intermittent intravenous administration schedule. Cancer Res 41: 2417
Chang P, Tamburini JM, Dodion P, Riggs CE Jr, Bachur NR (1983) In vitro metabolism of marcellomycin. Proc Am Assoc Cancer Res 4: 258
Crooke ST, DuVernay VH, Galvan L, and Prestayko AW (1978) Structure-activity relationships of anthracyclines relative to effects on macromolecular syntheses. Mol Pharmacol 14: 290
Dodion P, Riggs CE Jr, Tamburini JM, Nicaise C, Wathieu M, Rozencweig M, Bachur NR (1983) Human pharmacokinetics of marcellomycin. Proc Am Soc Clin Oncol 2: 32
Dodion P, Egorin MJ, Tamburini JM, Riggs CE, Bachur NR (1984) The murine metabolism and disposition of marcellomycin. Drug Metab Dispos 12: 209
DuVernay VH, Mong S, Crooke ST (1980) Molecular pharmacology of anthracyclines: demonstration of multiple mechanistic classes of anthracyclines. In: Crooke ST, Reich SD (eds) Anthracyclines: current status and new developments. Academic, New York, pp 61–123
Egorin MJ, Clawson RE, Ross LA, Chou FE, Andrews PA, Bachur NR (1980) Disposition and metabolism of N,N-dimethyldaunorubicin and N,N-dimethyladriamycin in rabbits and mice. Drug Metab Dispos 8: 353
Egorin MJ, Clawson RE, Ross LA, Chou FE, Andres PA, Bachur NR (1981) Disposition and metabolism of adriamycin octanoyl hydrazone (NSC 233853) in mice and rabbits. Drug Metab Dispos 9: 240
Egorin MJ, Van Echo DA, Fox BM, Whitacre M, Bachur NR (1982) Plasma kinetics of aclacinomycin A and its major metabolites in man. Cancer Chemother Pharmacol 8: 41
Egorin MJ, Andres PA, Nakazawa H, Bachur NR (1983a) Purification and characterization of aclacinomycin A and its metabolites from human urine. Drug Metab Dispos 11: 167
Egorin MJ, Clawson RE, Ross LA, Friedman RD, Reich SD, Pollak A, Bachur NR (1983b) Murine metabolism and disposition of iron: adriamycin complexes. Cancer Res 43: 3253
Fourcade A, Farhi JJ, Bennoun M, Goldschmidt E, Tapiero H (1983) Fate of aclacinomycin-A and its metabolites. Effect on cell growth and macromolecular synthesis. Biochem Pharmacol 32: 1819
Joss RA, Kaplan S, Goldhirsch A, Varini M, Brunner KW, Cavalli F (1983) A phase I trial of marcellomycin with a weekly dose schedule. Eur J Cancer Clin Oncol 19: 455
Karanes C, Young JD, Samson MK, Smith LB, Franco LA, Baker LH (1983) Phase I trial of aclacinomycin A: A clinical and pharmacokinetic study. Invest New Drugs 1: 173–179
Knott GD (1979) MLAB: A mathematical modeling tool. Comput Programs Biomed 10: 271–280
Majima H (1980) Preliminary clinical study of aclacinomycin A. Recent Results Cancer Res 70: 75–81
Mathé G, de Jager R, Hulhoven R, Delgado M, Machover D, Ribaud P, de Vassal F, Gil-Delgado M, Misset JL, Gouveia J, Jasmin C, Hayat M, Gastiaburu J, Schwarzenberg L (1982) L'aclacinomycine-A dans les leucémies aigües et les lymphomes non-hodgkiniens leucémiques. Nouv Presse Med 11: 25–28
Muggia FM, Rozencweig M (1980) Goals for new anthracyclines at the National Cancer Institute. In: Crooke ST, Reich SD (edsz) Anthracyclines: current status and new developments. Academic, New York pp 1–9
Nettleton DE, Bradner WT, Bush JA, Coon AB, Moseley JE, Myllymaki RW, O'Herron RA, Schreiber RH, Vulcano AL (1977) New antitumor antibiotics: Musettamycin and marcellomycin from bohemic acid complex. J Antibiot (Tokyo) 30: 525–529
Nicaise C, Rozencweig M, De Marneffe M, Crespeigne N, Dodion P, Piccart M, Sculier JP, Lenaz L, Kenis Y (1983) Clinical phase I trial of marcellomycin with a single-dose schedule. Eur J Cancer Clin Oncol 19: 449–454
Oki T, Takeuchi T, Oka S, Umezawa H (1980) New anthracycline antibiotic aclacinomycin A: Experimental studies and correlations with clinical trials. Recent Results Cancer Res 76: 21–40
Reich SD, Bradner WT, Rose WC, Schurig JE, Madissoo H, Johnson DF, Du Vernay VH, Crooke ST (1980) Marcellomycin. In: Crooke ST, Reich SD (eds), Anthracyclines: current status and new developments. Academic, New York, pp 343–364
Van Echo DA, Whitacre M, Aisner J, Applefeld MM, Wirnik PH (1982) Phase I trial of aclacinomycin A. Cancer Treat Rep 66: 1127–1132
von Hoff DD, Rozencweig M, Piccart M (1982) The cardiotoxicity of anticancer drugs. Semin Oncol 9: 23–40
Wooley PV III, Ayoob MJ, Levenson SM, Smith FP (1982) A phase I clinical trial of aclacinomycin A administered on a five-consecutive day schedule. J Clin Pharmacol 22: 359–365
Young RC, Ozols RF, Myers CE (1981) The anthracycline antineoplastic drugs. N Engl J Med 305: 139–153
Author information
Authors and Affiliations
Additional information
International Visiting Fellow at the National Institutes of Health (Bethesda, Md) and an International Fulbright Scholar (Washington, DC)
Rights and permissions
About this article
Cite this article
Dodion, P., Egorin, M.J., Riggs, C.E. et al. Comparative murine metabolism and disposition of class II anthracycline antibiotics. Cancer Chemother. Pharmacol. 15, 153–160 (1985). https://doi.org/10.1007/BF00257527
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00257527