Influence of amiodarone on genetically determined drug metabolism in humans

Amiodarone has been shown to interact with the nongenetically determined hepatic elimination of several drugs, including phenytoin and digoxin. Its influence on genetically determined metabolic pathways has not been studied in humans. We examined the effects of oral amiodarone therapy on the genetically determined metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450MEPH), and dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 ± 16 days after amiodarone (loading dose of 1000 mg/day for 10 days followed by a maintenance dose of 200 to 400 mg/day). Genetically determined enzyme activity was assessed indirectly by calculating the metabolic ratio (parent drug/metabolite in 8-hour urine for CYP2D6 and P450MEPH and N-acetylisoniazid/isoni-azid in plasma for N-acetyltransferase) after oral administration of the parent compounds. At the time of phenotyping, plasma concentrations of amiodarone and N-desethylamiodarone were 0.66 ± 0.35 µg/ml and 0.65 ± 0.26 µg/ml, respectively. Amiodarone increased the log(metabolic ratio) of dextromethorphan from a median of −2.5 (range, −2.9 to −2.0) to a median of −1.9 (range, −2.5 to −1.5; p < 0.02) but did not alter the metabolic ratio of mephenytoin or isoniazid. The amount of dextromethorphan excreted in urine increased from a median of 0.084 µmol/8 hours (range, 0.041 to 0.161 µmol/8 hours) to a median of 0.205 µmol/8 hours (range, 0.064 to 0.288 µmol/8 hours; p < 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 µmol/8 hours (range, 15 to 37 µmol/8 hours) to a median of 20 µmol/8 hours (range, 7 to 27 µmol/8 hours; p < 0.09). Additional in vitro studies in microsomes confirmed that amiodarone inhibits dextromethorphan O-demethylase activity. These findings suggest that amiodarone decreases the activity of CYP2D6 and may impair the elimination of drugs whose clearance depends on this cytochrome in extensive metabo-lizers of dextromethorphan. Clinical Pharmacology and Therapeutics (1991) 50, 259–266; doi:10.1038/clpt.1991.135