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Metabolic Disposition of 5-Iminodaunorubicin in the Rat¹

Life Sciences Division, SRI International, Menio Park, California 94025

We determined the metabolic disposition of 5-iminodaunorubicin (IMD) in rats receiving acute doses of IMD (16 and 4 mg/kg) i.v., i.p., and p.o. Major compounds found in plasma, liver, heart, lung, and brain of the rats receiving the higher dose, i.v. or i.p., were IMD and 5-imino-13-dihydrodaunorubicin. The aglycones, 5-iminodaunorubicinone and 5-imino-13-dihydrodaunorubicinone, were minor metabolites. No deoxyaglycones of IMD were detected in any tissue. We could not detect daunorubicin or its metabolites indicating IMD was not a prodrug of daunorubicin. Highest levels of IMD and metabolites were found in lung, liver, and heart, and lowest levels were found in the plasma and brain. Plasma levels of IMD after the higher i.v. dose decayed in a biphasic manner, and we calculated -phase and ß-phase half-times of decay of 1.4 and 10 hr, respectively. Patterns of distribution of IMD and metabolites were very similar following i.v. and i.p. treatments, except for higher amounts of IMD and metabolites in the liver after the latter route. A p.o. dose of IMD (16 mg/kg) yielded plasma levels of IMD that were only about 20% of those found by the parenteral routes. Summations of all compounds in all tissues at all times after this treatment yielded <2% of the corresponding totals found by the other routes. Results obtained following IMD (4 mg/kg) by the three routes generally confirmed conclusions derived from the studies at the higher dose, and we found an approximate linear dose relationship between the results from the two studies.

Our inability to detect the formation of deoxyaglycone metabolites of IMD in vivo is consistent with earlier in vitro findings that IMD does not participate in the oxygen-cycling phenomenon typical of daunorubicin and doxorubicin to form drug and oxygen radicals and deoxyaglycone metabolites.

¹ Presented in part at the 73rd Annual Meeting of the American Association for Cancer Research, St. Louis, MO, April 28 to May 1, 1982 (23). Supported by Cancer Research Emphasis Grant 5 R01-CA-25711.

² To whom requests for reprints should be addressed.

Received 7/11/83. Accepted 1/ 4/84.

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