Mitoxantrone Pharmacokinetics

Abstract

Mitoxantrone is the first fully synthesized anthrachinone derivative (1,4-dihydroxy-5,8-bis [[2-[(2-hydroxyethyl)amino] ethyl] amino]-9, 10-anthracenedione dihydrochloride, NSC 301,739), which was introduced into cancer therapy in the late 1970s. Since then it has been widely used for the treatment of advanced breast cancer, acute leukemia, malignant lymphomas, and hepatocellular carcinoma [11,12]. In spite of its extensive clinical application knowledge about the pharmacokinetic characteristics of Mitoxantrone including key parameters as the terminal elimination half-life and especially its main metabolism and excretion are still not fully elucidated. Hence, substantial differences in the values for the terminal elimination half-life emerge from a comparative analysis of previously published reports ranging from 3 to 215 h. Even less information is available about the pharmacokinetics of the mono- and dicarboxyacid derivatives of Mitoxantrone which are considered as its main metabolites. Data on the potential impact of these substances, which have no cytotoxic activity, on the kinetic of the parent compound are almost exclusively derived from animal models and not entirely investigated [1, 3, 4, 5, 6, 7, 8, 10, 11, 13, 14, 16, 17, 19, 20, 21, 22, 24, 25, 26, 28, 29, 30, 31]. In addition new metabolites of Mitoxantrone were recently identified in pleura fluid by our group and were characterized in more detail by Blanz et al. [6, 27]. These data strongly suggest that the degree of Mitoxantrone metabolism has been underestimated in previous investigations and that special attention must be directed to enravell the kinetic behaviour of the parent drug and its main metabolites.