Inhibitory effects of amiodarone and its <i>N</i>‐deethylated metabolite on human cytochrome P450 activities: Prediction of <i>in vivo</i> drug interactions

• K. Ohyama

• M. Nakajima

• M. Suzuki

• N. Shimada

• H. Yamazaki

• T. Yokoi

抄録

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+I u / K i values. Results  Amiodarone weakly inhibited CYP2C9, CYP2D6, and CYP3A4‐mediated activities with K i values of 45.1–271.6 μm. Desethylamiodarone competitively inhibited the catalytic activities of CYP2D6 ( K i =4.5 μm ) and noncompetitively inhibited CYP2A6 ( K i =13.5 μm ), CYP2B6 ( K i =5.4 μm ), and CYP3A4 ( K i =12.1 μm ). The catalytic activities of CYP1A1 ( K i =1.5 μm, α=5.7), CYP1 A 2 ( K i =18.8 μm, α=2.6), CYP2 C 9 ( K i =2.3 μm, α=5.9), and CYP2 C 19 ( K i =15.7 μm, α=4.5) were inhibited by desethylamiodarone with mixed type. The 1+I u / K i 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.

収録刊行物

• British Journal of Clinical Pharmacology

  British Journal of Clinical Pharmacology 49 (3), 244-253, 2000-03

  Wiley

キーワード

• Pharmacology (medical)
• Pharmacology

詳細情報

• CRID: 1364233271031627008
• NII論文ID: 80011675845
• DOI: 10.1046/j.1365-2125.2000.00134.x
• ISSN: 13652125
• ISSN: 03065251
• Web Site: https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1046%2Fj.1365-2125.2000.00134.x
• Web Site: https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2125.2000.00134.x
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  • CiNii Articles