Depressive effect of amiodarone on hepatic drug metabolism in the rat.
The effect of pretreatment of rats with three daily i.p. doses of 25, 50 and 100 mg/kg of the antiarrhythmic agent, amiodarone, on the activity of some hepatic drug metabolizing enzymes, on the levels of cytochromes P-450 and b5 as well as on lipid peroxidation is reported. Amiodarone at doses of 50 and 100 mg/kg significantly reduced the hydroxylation of aniline, the 0- and N-demethylations of p-nitroanisole and aminopyrine respectively and the level of cytochromes P-450. No inhibition in enzymic activity was observed with the 25 mg/kg dose. Testosterone hydroxylation was only depressed with the 100 mg/kg dose; in this case, all four hydroxylation reactions were reduced. Cytochrome b5 content and lipid peroxidation were significantly decreased with doses of 25 and 50 mg/kg. Addition of 1 mM of amiodarone to incubation mixtures containing either aminopyrine or p-nitroanisole or aniline only decreased aniline hydroxylation indicating that at high doses amiodarone acts as a competitive inhibitor of aniline hydroxylase but that the depressive effect observed on the 0- and N-demethylations of p-nitroanisole and aminopyrine is mediated via an indirect mechanism. The inhibitory effect of amiodarone was also shown in vivo by an increase in the elimination half-life and a decrease in the clearance of antipyrine. The results reported herein may explain, in part at least, the drug interactions recently reported in man with amiodarone.
D000633:Aminopyrine N-Demethylase / Q000037:antagonists & inhibitors; D000638:Amiodarone / Q000633:toxicity*; D000818:Animals; D001572:Benzofurans / Q000633:toxicity*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003864:Depression, Chemical; D004347:Drug Interactions; D066298:In Vitro Techniques; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009575:Nitroanisole O-Demethylase / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000378:metabolism
D001572:Benzofurans; D065607:Cytochrome P-450 Enzyme Inhibitors; D008054:Lipid Peroxides; D013739:Testosterone; D009575:Nitroanisole O-Demethylase; D000633:Aminopyrine N-Demethylase; D000638:Amiodarone