Anthracenedione antineoplastic agent effects on drug metabolism in vitro and in vivo: relationship between structure and mechanism of inhibition.
Two anthracenedione antineoplastic agents, mitoxantrone and the nonhydroxylated analog, ametantrone, were found to inhibit hepatic microsomal cytochrome P-450-dependent drug metabolism in vitro and in vivo. Ethoxycoumarin deethylase activity of phenobarbital-induced rabbit hepatic microsomes was inhibited 56 and 100% at 0.1 and 0.5 mM mitoxantrone, respectively, whereas activity was inhibited 38 and 88% at 0.1 and 0.5 mM ametantrone, respectively. Both mitoxantrone and ametantrone were noncompetitive inhibitors of ethoxycoumarin metabolism. Aryl hydrocarbon hydroxylase activity of hepatic microsomes was diminished 41 and 56% by 1 and 3 mM mitoxantrone, respectively; identical concentrations of ametantrone inhibited metabolism by 20 and 31%, respectively. In contrast to the inhibitory influence of both agents on monooxygenase activity, a differential effect on NADPH oxidation was observed. In the presence of benzo[alpha]-pyrene, mitoxantrone enhanced microsomal NADPH oxidation by 21%, whereas ametantrone produced a 22% decrease in cofactor oxidation relative to the control rate. The anthracenediones also inhibited hepatic cytochrome P-450-dependent monooxygenase activity in vivo, as evidenced by altered hexobarbital sleep times of mice. Mitoxantrone (20 and 40 mg/kg) prolonged sleep time by 59 and 68%, respectively; ametantrone (50 mg/kg) produced a 56% enhancement. These results demonstrate that both mitoxantrone and ametantrone inhibit drug metabolism in vitro and in vivo.
Kharasch, ED; Wendel, NK; Novak, RF
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