In vivo and in vitro effects of amrinone and milrinone on hepatic xenobiotic metabolism in rats

Studies were performed on the response of hepatic xenobiotic metabolizing enzymes to in vitro and in vivo exposure to amrinone and milrinone, two new inotropic compounds used in congestive heart failure. Both drugs exerted selective effects on various cytochrome P-450-dependent metabolic activities as well as conjugating pathways. Aminopyrine N-demethylation was selectively inhibited by in vitro addition of milrinone but not amrinone, and laurate hydroxylation was inhibited by both drugs. Cytosolic glutathione-S-transferase activity was profoundly inhibited by in vitro addition of both drugs. In vivo administration of either drug did not lead to significant inhibition of the pathways studied other than laurate hydroxylation which was depressed 20-30%. Irreversible binding of [¹⁴C]-amrinone-derived radioactivity to microsomal protein was partially NADPH-dependent. Inhibition by SKF 525-A, α-naphthoflavone and various antioxidants was observed. No binding of [¹⁴C]-milrinone-derived radioactivity was seen. It is suggested that amrinone may selectively inhibit certain hepatic drug-metabolizing enzymes through metabolic electrophilic intermediates.