DEPRESSIVE EFFECT OF AMIODARONE ON HEPATIC DRUG-METABOLISM IN THE RAT

  • 1 January 1984
    • journal article
    • research article
    • Vol. 44  (1) , 15-30
Abstract
The effect of pretreatment of rats with 3 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 cytochrome 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 O- 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 4 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 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 O- 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 may explain, at least in part, the drug interactions recently reported in man with amiodarone.