Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: prediction of in vivo drug interactions.

Article Details

Citation

Ohyama K, Nakajima M, Suzuki M, Shimada N, Yamazaki H, Yokoi T

Inhibitory effects of amiodarone and its N-deethylated metabolite on human cytochrome P450 activities: prediction of in vivo drug interactions.

Br J Clin Pharmacol. 2000 Mar;49(3):244-53. doi: 10.1046/j.1365-2125.2000.00134.x.

PubMed ID
10718780 [ View in PubMed
]
Abstract

AIMS: To predict the drug interactions of amiodarone and other drugs, the inhibitory effects and inactivation potential for human cytochrome P450 (CYP) enzymes by amiodarone and its N-dealkylated metabolite, desethylamiodarone were examined. METHODS: The inhibition or inactivation potency of amiodarone and desethylamiodarone for human CYP activities were investigated using microsomes from B-lymphoblastoid cell lines expressing CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. The in vivo drug interactions of amiodarone and desethylamiodarone were predicted in vitro using the 1+Iu/Ki values. RESULTS: Amiodarone weakly inhibited CYP2C9, CYP2D6, and CYP3A4-mediated activities with Ki values of 45.1-271.6 microm. Desethylamiodarone competitively inhibited the catalytic activities of CYP2D6 (Ki=4.5 microm ) and noncompetitively inhibited CYP2A6 (Ki=13.5 microm ), CYP2B6 (Ki=5.4 microm ), and CYP3A4 (Ki=12.1 microm ). The catalytic activities of CYP1A1 (Ki=1.5 microm, alpha=5.7), CYP1A2 (Ki=18.8 microm, alpha=2.6), CYP2C9 (Ki=2.3 microm, alpha=5.9), and CYP2C19 (Ki=15.7 microm, alpha=4.5) were inhibited by desethylamiodarone with mixed type. The 1+Iu/Ki values of desethylamiodarone were higher than those of amiodarone. Amiodarone inactivated CYP3A4, while desethylamiodarone inactivated CYP1A1, CYP1A2, CYP2B6, and CYP2D6. CONCLUSIONS: The interactions between amiodarone and other drugs might occur via the inhibition of CYP activities by its N-dealkylated metabolite, desethylamiodarone, rather than by amiodarone itself. In addition, the inactivation of CYPs by desethylamiodarone as well as by amiodarone would also contribute to the drug interactions.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
AmiodaroneCytochrome P450 2A6ProteinHumans
Unknown
Inhibitor
Details
AmiodaroneCytochrome P450 2C19ProteinHumans
Unknown
Substrate
Inhibitor
Details
AmiodaroneCytochrome P450 2D6ProteinHumans
No
Inhibitor
Details
AmiodaroneCytochrome P450 3A4ProteinHumans
No
Substrate
Inhibitor
Details