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Excretion and Metabolism of Mitoxantrone in Rabbits¹

INSERM U-278, Laboratoire Hospitalo-Universitaire de Toxicocinétique et de Pharmacocinétique, Faculté de Pharmacie, 27 Boulevard Jean Moulin, 13385 Marseille, Cédex 5, France; and Institut I. Paoli-J. Calmettes, 232 Boulevard de S^te Marguerite, 13273 Marseille, Cédex 9, France

The hepatic clearance of mitoxantrone was evaluated in rabbits using both bile-duct cannulated animals and freshly isolated hepatocytes in suspension or in primary culture. Mitoxantrone metabolic behavior was assessed by high-performance liquid chromatography using a method which specifically resolved mitoxantrone from its mono- and dicarboxylic acid derivatives. Excretion of mitoxantrone in bile and urine was studied over a 6-h period of observation following i.v. bolus injection of 0.04, 0.20, and 1.0 mg [¹⁴C]mitoxantrone/kg. Bile route represented the main excretion pathway for mitoxantrone and its metabolites—mainly the monocarboxylic acid derivative. Biliary excretion was very rapid (maximum biliary concentration achieved 9 to 18 min following drug administration) and amounted to 29.5 ± 9.3%, 27.6 ± 7.9%, and 28.3 ± 3.8% of administered drug, respectively. Urinary excretion amounted to 7.3 ± 0.2%, 7.1 ± 4.6%, and 6.0 ± 1.5%, respectively. Both biliary and urinary excretions of mitoxantrone and its metabolites remained linear over the range of concentrations routinely used in clinic. Metabolism of mitoxantrone was first studied using rabbit hepatocytes in suspension. Since metabolic rate was slow under these incubation conditions (observation period, 1 h), mitoxantrone metabolism was investigated in primary cultures of rabbit hepatocytes. Mitoxantrone was rapidly accumulated within the cells and metabolized to its various metabolites which rapidly effluxed in the extracellular medium. After a 48-h exposure of hepatocytes to a broad range of mitoxantrone concentrations (1 to 20 µM), it could be seen that (a) drug accumulation and metabolism did not exhibit saturation processes, (b) mitoxantrone was the main intracellular form, while (c) metabolites rapidly effluxed in the extracellular compartment and (d) the monocarboxylic acid derivative represented the main extracellular metabolite. This data demonstrates the important role played by the liver in the pharmacokinetic behavior of mitoxantrone and suggests a careful drug monitoring in patients with severe liver dysfunction.

¹ This research was supported by Lederle-INSERM Grant 86-009 and by grants from "La Fédération Nationale des Centres de Lutte Contre le Cancer" and "La Fédération Départmentale des Bouches du Rhône des Centres de Lutte Contre le Cancer."

² Present address: Sanofi Recherche, 32, Rue du Pr. J. Blayac, 34082 Montpellier Cédex, France.

³ To whom requests for reprints should be addressed.

Received 10/13/87. Revised 6/14/88. Revised 9/20/88. Accepted 10/13/88.