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Hepatobiliary Metabolism and Excretion of Adriamycin and N-Trifluoroacetyladriamycin-14-valerate in the Rat¹

The Sidney Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

In connection with mechanism of action studies with N-trifluoroacetyladriamycin-14-valerate (AD 32), a superior Adriamycin (ADR) analog under development in these laboratories, serial bile samples were collected from male Sprague-Dawley rats given a single i.v. dose of either ADR (4 mg/kg) or AD 32 (20 mg/kg) and were analyzed for anthracyclines by thin-layer chromatography-fluorometry and high-performance liquid chromatography. For ADR, 20% of the administered dose was accounted for at 24 hr, whereas 80% of the AD 32 dose was excreted into the bile by this time. ADR underwent little biotransformation; 80% of the 48-hr cumulative fluorescence excretion was attributable to unchanged drug, one-half the remainder was adriamycinol, and the balance was polar conjugates. In contrast, AD 32 underwent extensive metabolism to N-trifluoroacetyladriamycin, N-trifluoroacetyladriamycinol, and polar conjugates, mostly glucuronides of N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol. Based on direct and indirect evidence, ADR was not a metabolite of AD 32.

¹ Supported in part by Research Grants CA 17263 and CA 19118 from the National Cancer Institute, Department of Health, Education and Welfare. A preliminary report of this work has appeared (22).

² To whom requests for reprints should be addressed, at the Division of Medicinal Chemistry and Pharmacology, Sidney Farber Cancer Institute, 35 Binney St., Boston, Mass. 02115.

³ Visiting Professor, July 1976 to May 1977. Present address: Christie Hospital, Wilmslow Road, Manchester 20, England.

⁴ Recipient of National Research Service Award CA 05130 from the National Cancer Institute.

Received 5/31/77. Accepted 11/ 7/77.

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