Abstract
It has been reported that the 9‐aminoanthracycline amrubicin shows good efficacy in human tumor xenograft models. We studied the disposition and metabolism of amrubicin in mice, in comparison with those of doxorubicin. Amrubicinol, a 13‐hydroxy metabolite of amrubicin, which is 10 to 100 times more cytotoxic than amrubicin, was detected as a major metabolite in blood and tissues, and aglycones of amrubicin were also detected. A pharmacokinetic study revealed that amrubicin had a smaller distribution volume and a shorter half‐life than doxorubicin. In several normal tissues, the levels of amrubicin and amrubicinol were lower than those of doxorubicin. In contrast, the tumor levels of amrubicinol in the mice treated with amrubicin were higher than those of doxorubicin in the mice treated with that drug, in tumors that are sensitive to amrubicin. These results suggest that the potent therapeutic activity of amrubicin is caused by the selective distribution of its highly active metabolite, amrubicinol, in tumors.
Keywords: Anthracycline, Amrubicin, SM‐5887, Active metabolite, Tissue distribution
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REFERENCES
- 1. ) Ishizumi , K. , Ohashi , N. and Tanno , N.Stereospecific total synthesis of 9‐aminoanthracyclines: (+)‐9‐amino‐9‐deoxydaunomycin and related compounds . J. Org. Chem. , 52 , 4477 – 4485 ( 1987. ). [Google Scholar]
- 2. ) Morisada , S. , Yanagi , Y. , Noguchi , T. , Kashiwazaki , Y. and Fukui , M.Antitumor activities of a novel 9‐aminoanthracycline (SM‐5887) against mouse experimental tumors and human tumor xenografts . Jpn. J. Cancer Res. , 80 , 69 – 76 ( 1989. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. ) Yokota , S. , Negoro , S. , Yana , T. , Takada , Y. , Fukuoka , M.and The West Japan Lung Cancer Group. Phase II study of amrubicin (SM‐5887), a novel 9‐aminoanthracycline, in previously untreated patients with extensive‐stage small‐cell lung cancer (ES‐SCLC): a trial of The West Japan Lung Cancer Group . 8th World Conference on Lung Cancer , A1576 ( 1997. ). [Google Scholar]
- 4. ) Hiraki , S. , Shinkai , T. , Furuse , K. , Fukuoka , M. , Ohnoshi , T. , Kimura , I.and The SM‐5887 Lung Cancer Study Group. A phase II of SM‐5887, a novel 9‐aminoanthracycline, for non‐small cell lung cancer . 18th International Congress of Chemotherapy , æ 726 ( 1993. ). [Google Scholar]
- 5. ) Yesair , W. , Schwartzbach , E. , Shuck , D. , Denine , E. P. and Asbell , A.Comparative pharmacokinetics of daunomycin and adriamycin in several animal species . Cancer Res. , 32 , 1177 – 1183 ( 1972. ). [PubMed] [Google Scholar]
- 6. ) Yamaoka , T. , Hanada , M. , Ichii , S. , Morisada , S. , Noguchi , T. and Yanagi , Y.Cytotoxicity of amrubicin, a novel 9‐aminoanthracycline, and its active metabolite amrubicinol on human tumor cells . Jpn. J. Cancer Res. , 89 , 1061 – 1067 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. ) Kuffel , J. , Reid , M. and Ames , M.Anthracyclines and their C‐13 alcohol metabolites: growth inhibition and DNA damage following incubation with human tumor cells in culture . Cancer Chemother. Pharmacol. , 30 , 51 – 57 ( 1992. ). [DOI] [PubMed] [Google Scholar]
- 8. ) Ozols , F. , Willson , V. , Weltz , D. , Grotzinger , R. , Myers , E. and Young , C.Inhibition of human ovarian cancer colony formation by adriamycin and its metabolites . Cancer Res. , 40 , 4109 – 4112 ( 1980. ). [PubMed] [Google Scholar]
- 9. ) Yesair , D. , Thayer , P. , McNitt , S. and Teague , K.Comparative uptake, metabolism and retention of anthracyclines by tumors growing in vitro and in vivo . Eur. J. Cancer , 16 , 901 – 907 ( 1980. ). [DOI] [PubMed] [Google Scholar]
- 10. ) Toffoli , G. , Corona , G. , Simone , F. , Gigante , M. , Angeli , S. and Boiocchi , M.Cellular pharmacology of idarubicinol in multidrug‐resistant LoVo cell lines . Int. J. Cancer , 67 , 129 – 137 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 11. ) Matsushita , Y. , Iguchi , H. , Kiyosaki , T. , Tone , H. and Ishikura , T.A high performance liquid chromatographic method of analysis of 4′‐O‐tetrahydropyranyladriamycin and their metabolites in biological samples . J. Antibiot. , 36 , 880 – 886 ( 1983. ). [DOI] [PubMed] [Google Scholar]
- 12. ) Iguchi , H. , Tone , H. , Ishimura , T. , Takeuchi , T. and Umezawa , H.Pharmcokinetics and disposition of 4′‐O‐tetrahydropyranyladriamycin in mice by HPLC analysis . Cancer Chemother. Pharmacol. , 15 , 132 – 140 ( 1985. ). [DOI] [PubMed] [Google Scholar]
- 13. ) Yamaoka , K. , Tanigawara , Y. , Nakagawa , T. and Uno , T.A pharmacokinetic analysis program (MULTI) for micro‐computer . J. Pharmacobiodyn. , 4 , 879 – 885 ( 1981. ). [DOI] [PubMed] [Google Scholar]
- 14. ) Cusack , J. , Young , P. and Olson , D.Daunorubicin and daunorubicinol pharmacokinetics in plasma and tissues in the rat . Cancer Chemother. Pharmacol. , 35 , 213 – 218 ( 1995. ). [DOI] [PubMed] [Google Scholar]
- 15. ) Reid , M. , Pendergrass , W. , Krailo , D. , Hammond , D. and Ames , M.Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Children's Cancer Study Group report . Cancer Res. , 50 , 6525 – 6528 ( 1990. ). [PubMed] [Google Scholar]
- 16. ) Zanette , L. , Zucchetti , M. , Freshi , A. , Erranti , D. , Tirelli , U. and D'Incalci , M.Pharmacokinetics of 4‐demethoxy‐daunorubicin in cancer patients . Cancer Chemother. Pharmacol. , 25 , 445 – 448 ( 1990. ). [DOI] [PubMed] [Google Scholar]
- 17. ) Boven , E. , Jong , J. , Kuiper , M. , Bast , A. and Vijgh , F.Relationship between the tumor tissue pharmacokinetics and the antiproliferative effects of anthracyclines and their metabolites . Eur. J. Cancer , 32A , 1382 – 1387 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 18. ) Shinkai , H. , Takahashi , H. , Miyamoto , K. , Uchida , T. and Tokiwa , T.Comparative pharmacokinetics of KRN8602, a new morpholino anthracycline, and Adriamycin in tumor‐bearing mice . Cancer Chemother. Pharmacol. , 38 , 417 – 424 ( 1996. ). [DOI] [PubMed] [Google Scholar]
- 19. ) Noguchi , T. , Ichii , S. , Morisada , S. , Yamaoka , T. and Yanagi , Y.In vivo efficacy and tumor‐selective metabolism of amrubicin to its active metabolite . Jpn. J. Cancer Res. , 89 , 1055 – 1060 ( 1998. ). [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. ) Jong , J. , Schoofs , R. , Snabilie , M. , Bast , A. and Vijgh , F.The role of biotransformation in anthracycline‐induced cardiotoxicity in mice . J. Pharmacol. Exp. Ther. , 266 , 1312 – 1320 ( 1993. ). [PubMed] [Google Scholar]
- 21. ) Cusack , J. , Mushlin , S. , Vouleilis , D. , Li , X. , Boucek , J. and Olson , D.Daunorubicin‐induced cardiac injury in the rabbit: a role for daunorubicinol ? Toxicol. Appl. Pharmacol. , 118 , 177 – 185 ( 1993. ). [DOI] [PubMed] [Google Scholar]
- 22. ) Suzuki , T. , Minamide , S. , Iwasaki , T. , Yamamoto , H. and Kanda , H.Cardiotoxicity of a new anthracycline derivative (SM‐5887) following intravenous administration to rabbits: comparative study with doxorubicin . Invest. New Drugs , 15 , 219 – 225 ( 1997. ). [DOI] [PubMed] [Google Scholar]