HEPATOBILIARY METABOLISM AND EXCRETION OF ADRIAMYCIN AND N-TRIFLUOROACETYLADRIAMYCIN-14-VALERATE IN RAT

Abstract

In connection with mechanism of action studies with the antitumor agent 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 ADR (4 mg/kg) or AD 32 (20 mg/kg) and were analyzed for anthracyclines by TLC-fluorometry and high-performance liquid chromatography. For ADR, 20% of the administered dose was accounted for at 24 h, whereas 80% of the AD 32 dose was excreted into the bile by this time. ADR underwent little biotransformation; 80% of the 48-h cumulative fluorescence excretion was attributable to unchanged drug, 1/2 the remainder was adriamycinol and the balance was polar conjugates. AD 32 underwent extensive metabolism to N-trifluoroacetyladriamycin, N-trifluoroacetyladriamycinol and polar conjugates, mostly glucuronides of N-trifluoroacetyladriamycinol. Based on direct and indirect evidence, ADR was not a metabolite of AD 32.