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Disposition of 14C-labelled 4′-epidoxorubicin and doxorubicin in the rat

A comparative study

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The disposition of 4′-epi-[14-14C]doxorubicinHCl (4′-epi-[14C]DXR) and [14-14C]doxorubicinHCl ([14C]DXR) was studied in male Sprague-Dawley rats given 1 mg/kg body weight IV. Most of the radioactivity administered was recovered in the faeces (two-thirds of the dose within 6 days after administration), urine accounting for 15% of the 14C given during the same period. A significant amount of radioactivity was also found in expered air. Significantly higher levels of radioactivity were recorded in the plasma (40 min and 4 h) and liver (40 min) in [14C]DXR-treated animals, whereas in animals treated with 4′-epi-[14C]DXR a higher specific radioactivity was found in the kidneys (40 min and 4 h) and bone marrow (40 min). The total tissue residual radioactivity was greater (P (0.05) at 24 h for [14C]DXR (45.8%) than for 4′-epi-[14C]DXR (38.6%).

The main radioactive species in urines were the unchanged drugs. Minor metabolites were represented by a polar fraction, 13-dihydroderivatives, and aglycones. Whereas aglycones represent an important fraction of extractable tissue radioactivity in liver samples of many of the treated animals, the unchanged drug was invariably the major radioactive component in spleen, lung, and kidney. Liver extraction studies showed the presence of significant amounts of bound radioactivity that could be recovered in soluble form only after incubation with deoxyribonuclease.

The main radioactive species present in the bile were the unchanged drug and a polar fraction. The amount of the former was higher in [14C]DXR-treated than in 4′-epi-[14C]DXR-treated animals. On the other hand, partial glucuronidation of 4′-epi-[14C]DXR was deduced on the basis of results of enzymic hydrolysis of bile samples.

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  1. 1.

    Arcamone F (1981) Doxorubicin, anticancer antibiotics. Academic Press, New York (Medicinal Chemistry Series, vol 17)

  2. 2.

    Arcamone F, Franceschi G, Penco S (1974) Adriamycin 14-esters. US Patent 3,803,124 April 9, 1974

  3. 3.

    Bachur NR, Gee M (1976) Microsomal reductive glycosidase. J Pharmacol Exp Ther 197: 681

  4. 4.

    Blatt AH (1964) Organic synthesis, collective vol 2. Wiley, New York, pp 165 and 461

  5. 5.

    Broggini M, Colombo T, Martini A, Donelli MG (1980) Studies on the comparative distribution and biliary excretion of doxorubicin and 4′-epidoxorubicin in mice and rats. Cancer Treat Rep 64: 897

  6. 6.

    Buyniski JP, Hirth RS (1980) Anthracycline cardiotoxicity in the rat. In: Crooke ST, Reich SD (eds) Anthracyclines: Current status and new developments. Academic Press, New York, p 157

  7. 7.

    Casazza AM, Di Marco A, Bertazzoli C, Formelli F, Giuliani F, Pratesi G (1978) Antitumor activity, toxicity and pharmacological properties of 4′-epiadriamycin. In: Siegenthaler W, Luthy R (eds) Current chemotherapy vol 2. American Society for Microbiology, Washington, p 1257

  8. 8.

    Casazza AM, Di Marco A, Bonadonna G, Bonfante V, Bertazzoli C, Bellini O, Pratesi G, Sala L, Ballerini L (1980) Effects of modifications in position 4 of the chromophore or in position 4′ of the aminosugar, on the antitumor activity and toxicity of daunorubicin and doxorubicin. In: Crooke ST, Reich SD (eds) Anthracyclines: Current status and new developments. Academic Press, New York, p 403

  9. 9.

    Chang BK (1982) Tissue distribution of adriamycin administered intraperitoneally vs. intravenously with special emphasis on the pancreas. Bull Cancer 69: 172

  10. 10.

    Felsted RL, Gee M, Bachur NR (1974) Rat liver daunorubicin reductase. J Biol Chem 249: 3672

  11. 11.

    Felsted RL, Richter DR, Bachur NR (1977) Rat liver aldehyde reductase. Biochem Pharmacol 26: 1117

  12. 12.

    Fujimoto JM, Haarstad VB (1969) The isolation of morphine ethereal sulfate from urine of the chicken and cat. J Pharmacol Exp Ther 16: 45

  13. 13.

    Israel M, Wilkinson MP, Pegg WJ, Frei E III (1978) Hepatobiliary metabolism and excretion of adriamycin and N-trifluoroacetyl-adriamycin-14-valerate in the rat. Cancer Res 38: 365

  14. 14.

    Liss RH, Yesair DW, Schepis JP, Marenchich JC (1977) Distribution of adriamycin and daunomycin in rats. Acta Pharmacol Toxicol [Suppl 1] 41: 128

  15. 15.

    Loveless H, Arena E, Felsted RL, Bachur NR (1978) Comparative mammalian metabolism of adriamycin and daunorubicin. Cancer Res 38: 593

  16. 16.

    Olson HM (1980) The rat as a model system for evaluating anthracycline cardiotoxicity. In: Crooke ST, Reich SD (eds) Anthracyclines: Current status and new developments. Academic Press, New York, p 171

  17. 17.

    Parker RJ, Priester ER, Sieber SM (1982) Effect of route administration and liposome entrapment on the metabolism and disposition of adriamycin in the rat. Drug Metabl Dispos 10: 499

  18. 18.

    Penco S, Vicario GP, Angelucci F, Arcamone F (1977) Synthesis of [14 14C]daunorubicin and doxorubicin. J Antibiot (Tokyo) 30: 773

  19. 19.

    Peters JH, Gordon GR, Kashiwase D, Acton EM (1981) Tissue distribution of doxorubicin and doxorubicinol in rats receiving multiple doses of doxorubicin. Cancer Chemother Pharmacol 7: 65

  20. 20.

    Philips FS, Gilladoga A, Marquardt H, Sternberg SS, Vidal PM (1975) Some observation on the toxicity of adriamycin. Cancer Chemother Rep [3] 6: 177

  21. 21.

    Schwartz HS, Parker NB (1981) Initial biotransformations of daunorubicin to aglycones by rat liver microsomes. Cancer Res 4: 2343

  22. 22.

    Sonneveld P, Van Bekkum DW (1981) Different distribution of adriamycin in normal and leukaemic rats. Br J Cancer 43: 464

  23. 23.

    Tavoloni N, Guarino AM (1980a) Bile secretory function: a determinant of adriamycin disposition. Arch Int Pharmacodyn Ther 245: 180

  24. 24.

    Tavoloni N, Guarino AM (1980b) Biliary and urinary excretion of adriamycin in anesthetized rats. Pharmacology 20: 256

  25. 25.

    Tavoloni N, Guarino AM (1980c) Disposition and metabolism of adriamycin in the rat. J Pharm Dyn 21: 244

  26. 26.

    Terasaki T, Iga T, Sugiyama Y, Hanano M (1982a) Quantitative evidence for interspecies difference in tissue distribution mechanism of adriamycin. J Pharm Dyn 5: S-67

  27. 27.

    Terasaki T, Iga T, Sugiyama Y, Hanano M (1982b) Experimental evidence of characteristic tissue distribution of adriamycin. Tissue DNA concentrations as a determinant. J Pharm Pharmacol 8: 597

  28. 28.

    Wilkinson PM, Mawer GE (1974) The peristence of adriamycin in man and rat. Br J Clin Pharmacol 1: 241

  29. 29.

    Wilkinson PM, Israel M, Pegg WJ, Frei E III (1979) Comparative. metabolism and excretion of adriamycin in man, monkey and rat. Cancer Chemother Pharmacol 2: 121

  30. 30.

    Vicario GP, Penco S, Arcamone F (1980) Daunorubicin and doxorubicin labelled with 14C at the 14 position and processes for their preparation. US Patent 4,211,864 July 8, 1980

  31. 31.

    Yesair DW, Schwartzbach E, Shuck D, Denine EP, Asbell MA (1972) Comparative pharmacokineties of daunomycin and adriamycin in several animal species. Cancer Res 32: 1177

  32. 32.

    Zbinden G, Brändle E (1975) Toxicologic screening of daunorubicin (NSC-82151), adriamycin (NSC-123127) and their derivatives in rats. Cancer Chemother Rep [1] 59: 707

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Correspondence to Gian Piero Vicario.

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Arcamone, F., Lazzati, M., Vicario, G.P. et al. Disposition of 14C-labelled 4′-epidoxorubicin and doxorubicin in the rat. Cancer Chemother. Pharmacol. 12, 157–166 (1984).

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  • Doxorubicin
  • Enzymic Hydrolysis
  • Liver Sample
  • Extractable Tissue
  • Unchanged Drug