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Comparative pharmacokinetics and metabolism of doxorubicin and 4-demethoxy-4′-O-methyldoxorubicin in tumor-bearing mice

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Summary

It has been reported that 4-demethoxy-4′-O-methyldoxorubicin (4-dm-4′-O-methylDX) is more potent than doxorubicin (DX), equally active in some murine leukemias and solid tumors, and almost devoid of cardiotoxicity. We used HPLC to investigate the metabolism and the disposition of this drug in comparison with DX in mice bearing colon 38 adenocarcinoma SC and treated with IV doses of the two drugs that were equiactive and equitoxic (4-dm-4′-O-methylDX 1 mg/kg; DX 10 mg/kg). 4-Dm-4′-O-methylDX was metabolized to a polar metabolite, presumably 4-demethoxyDX, which was eliminated more slowly than the parent drug from all the organs and accounted for 25%–50% of total fluorescence; traces of two metabolites less polar than the parent drug (2% of total fluorescence) were found only at early times in the liver. In DX-treated mice traces of doxorubicinol (1%–3% of total fluorescence) were found in tumor and organs, and two aglycones were detected only at early times in the liver. In plasma both drugs declined biexponentially and 4-dm-4′-O-methylDX was eliminated slightly faster than DX. The rate of elimination of the new analogue from lung, kidney, spleen, and small intestine was faster than that of DX; in heart and liver 4-dm-4′-O-methylDX was detectable for only up to 24 h, while DX was detectable for up to 7 days. In the tumor the kinetics and the elimination patterns of the two drugs were similar. The distribution of 4-dm-4′-O-methylDX, as a percentage of the administered dose, was 1.3–2 times higher than that of DX in the organs and 3 times higher in the tumor, which suggests an improved selectivity of the new analogue for the tumor compared with DX.

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References

  1. 1.

    Bachur NR, Egorin MJ, Hildebrand RC (1973) Daunorubicin and adriamycin metabolism in the golden Syrian hamster. Biochem Med 8: 352

  2. 2.

    Bachur NR, Hildebrand RC, Jaenke RS (1974) Adriamycin and daunorubicin disposition in the rabbit. J Pharmacol Exp Ther 191: 331

  3. 3.

    Bolanowska W, Gessner T (1982) Body residue and metabolism of adriamycin and daunorubicin in control and phenobarbital-pretreated mice. Xenobiotica 12:125

  4. 4.

    Brown JE, Wilkinson PA, Brown JR (1981) Rapid high-performance liquid chromatographic assay for the anthracyclines daunorubicin and 7-con-O-methylnogarol in plasma. J Chromatogr 226: 521

  5. 5.

    Chan KK, Chlebowski RT, Tong M, Chen H-SG, Gross JF, Bateman JR (1980) Clinical pharmacokinetics of adriamycin in hepatoma patients with cirrhosis. Cancer Res 40: 1263

  6. 6.

    Di Marco A, Casazza AM, Giuliani F, Pratesi G, Arcamone F, Bernardi L, Franchi G, Giardino P, Patelli B, Penco C (1978) Synthesis and antitumor activity of 4-demethoxyadriamycin and 4-demethoxy-4′-epi-adriamycin. Cancer Treat Rep 62: 375

  7. 7.

    Formelli F, Casazza AM, Di Marco A, Mariani A, Pollini C (1979) Fluorescence assay of tissue distribution of 4-demethoxydaunorubicin and 4-demethoxydoxorubicin in mice bearing solid tumors. Cancer Chemother Pharmacol 3:261

  8. 8.

    Formelli F, Pollini C, Casazza AM, Di Marco A, Mariani A (1981) Fluorescence assay and pharmacokinetic studies of 4′-dexydoxorubicin and doxorubicin in organs of mice bearing solid tumors. Cancer Chemother Pharmacol 5: 139

  9. 9.

    Giuliani FC, Barbieri B, Bellini O, Podestà A, Kaplan NO, Casazza AM (1983) Antitumor activity and cardiotoxicity in mice of a new doxorubicin analog: 4-demethoxy-4′-O-methyldoxorubicin. 13th International Chemotherapy Congress, 12.4 1983, pp 8–17

  10. 10.

    Marquardt DW (1966) Least-squares estimation of nonlinear parameters, a computer program in FORTRAN IV language. IBM Share Library, 309401

  11. 11.

    Paul C, Baurain R, Gahrton G, Peterson C (1980) Determination of daunorubicin and its main metabolites in plasma, urine and leukaemic cells in patients with acute myeloblastic leukaemia. Cancer Lett 9: 263

  12. 12.

    Penco S, Casazza AM, Franchi G, Barbieri B, Bellini O, Podestà A, Savi G, Pratesi G, Geroni G, Di Marco A, Arcamone F (1983) Synthesis, antitumor activity and cardiac toxicity of new 4-demethoxyanthracyclines. Cancer Treat Rep 67: 665

  13. 13.

    Riggs CE Jr, Benjamin RS, Serpick AA, Bachur NR (1977) Biliary disposition of adriamycin. Clin Pharmacol Ther 22: 234

  14. 14.

    Schwartz HS (1973) A fluorimetric assay for daunomycin and adriamycin in animal tissues. Biochem Med J 7: 396

  15. 15.

    Spill J, Splitter G, Lalich J, et al (1980) Adriamycin cardiotoxicity: a comparison with 4-demethoxyadriamycin hydrochloride (NSC 256438). Roltech Scientific Services, Madison, p 1

  16. 16.

    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

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Author information

Correspondence to Franca Formelli.

Additional information

The work described in this paper was supported by grant N. 84.00855.44 of the ‘Oncologia’ project of the Consiglio Nazionale delle Ricerche, Rome, Italy

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Formelli, F., Carsana, R. & Pollini, C. Comparative pharmacokinetics and metabolism of doxorubicin and 4-demethoxy-4′-O-methyldoxorubicin in tumor-bearing mice. Cancer Chemother. Pharmacol. 16, 15–21 (1986). https://doi.org/10.1007/BF00255280

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Keywords

  • Leukemia
  • Adenocarcinoma
  • Cancer Research
  • Doxorubicin
  • Small Intestine