Anthracenedione Antineoplastic Agent Effects on Drug Metabolism in Vitro and in Vivo: Relationship between Structure and Mechanism of Inhibition

Anthracenedione Antineoplastic Agent Effects on Drug Metabolismin Vitro and in Vivo:Relationship between Structure and Mechanismof Inhibition. KHARASCH, E. D., WENDEL, N. K., AND NOVAK, R.F. (1987). Fundam. Appl Toxicol. 9, 18–25. Two anthracenedioneantineoplastic agents, mitoxantrone and the nonhydroxylatedanalog, ametantrone, were found to inhibit hepatic microsomalcytochrome P-450-dependent drug metabolism in vitro and in vivo.Ethoxycoumarin deethylase activity of phenobarbital-inducedrabbit hepatic microsomes was inhibited 56 and 100% at 0.1 and0.5 mM mitoxantrone, respectively, whereas activity was inhibited38 and 88% at 0.1 and 0.5 mM ametantrone, respectively. Bothmitoxantrone and ametantrone were noncompetitive inhibitorsof ethoxycoumarin metabolism. Aryl hydrocarbon hydroxylase activityof hepatic microsomes was diminished 41 and 56% by 1 and 3 mMmitoxantrone, respectively; identical concentrations of ametantroneinhibited metabolism by 20 and 31%, respectively. In contrastto the inhibitory influence of both agents on monooxygenaseactivity, a differential effect on NADPH oxidation was observed.In the presence of benzo[]-pyrene, mitoxantrone enhanced microsomalNADPH oxidation by 21%, whereas ametantrone produced a 22% decreasein cofactor oxidation relative to the control rate. The anthracenedionesalso inhibited hepatic cytochrome P-450-dependent monooxygenaseactivity in vivo, as evidenced by altered hexobarbital sleeptimes of mice. Mitoxantrone (20 and 40 mg/kg) prolonged sleeptime by 59 and 68%, respectively; ametantrone (50 mg/kg) produceda 56% enhancement. These results demonstrate that both mitoxantroneand ametantrone inhibit drug metabolism in vitro and in vivo.