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Comparative Mammalian Metabolism of Adriamycin and Daunorubicin

Laboratory of Clinical Biochemistry, Baltimore Cancer Research Center, Division of Cancer Treatment, National Cancer Institute, NIH, Baltimore, Maryland 21211

Both Adriamycin and daunorubicin undergo carbonyl reduction and glycosidic cleavage. We have investigated kinetic parameters of these reactions with several mammalian species including humans.

Adriamycin and daunorubicin showed similar K_m values for reduction in all organs studied except those from rabbits. Both rabbit liver and kidney have a much lower K_m for Adriamycin reduction. In contrast to the great similarity in K_m's, the V_max's varied greatly according to drug, organ, and species. Daunorubicin showed a greater V_max than did Adriamycin in all organs studied. The V_max ratio of daunorubicin to Adriamycin ranged from 159 to 178 in mice and rats to 10 to 30 in humans. Liver and kidney always showed greater activity than did cardiac or skeletal muscle. These enzymatic data correlate with the quicker in vivo reduction of daunorubicin than of Adriamycin, with a greater percentage of daunorubicin than Adriamycin excreted in the reduced form, than and, inversely, with clinical efficacy in that Adriamycin has a wider spectrum of antitumor activity.

All organs showed high levels of glycosidic cleavage in the absence of oxygen. In vivo, relatively little of either Adriamycin or daunorubicin is in the aglycone form. Thus, tissues, especially liver, have a great potential for glycosidic activity that is normally not exhibited. However, in certain patients this may be an important mechanism of biotransformation.

Although the role of these activities in normal cellular physiology is unknown, their ubiquity points toward an essential function.

¹ NATO Scholar. Istituto di Farmacolgia, Policlinico-Filiciuzza, 90127 Palermo, Italy. Deceased December 12, 1977.

Received 1/ 8/75. Accepted 11/17/77.

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