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/isoniazid 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 micrograms/ml and 0.65 +/- 0.26 micrograms/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 less than 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 mumol/8 hours (range, 0.041 to 0.161 mumol/8 hours) to a median of 0.205 mumol/8 hours (range, 0.064 to 0.288 mumol/8 hours; p less than 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 mumol/8 hours (range, 15 to 37 mumol/8 hours) to a median of 20 mumol/8 hours (range, 7 to 27 mumol/8 hours; p less than 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)
Funck-Brentano
C
C
Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
Jacqz-Aigrain
E
E
Leenhardt
A
A
Roux
A
A
Poirier
J M
JM
Jaillon
P
P
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000188:drug therapy / Q000378:metabolism; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D003915:Dextromethorphan / Q000378:metabolism; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008617:Mephenytoin / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype
D003915:Dextromethorphan; D003577:Cytochrome P-450 Enzyme System; D001191:Arylamine N-Acetyltransferase; C036116:desethylamiodarone; D000638:Amiodarone; D008617:Mephenytoin; D007538:Isoniazid