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

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+I u /K i values. Results Amiodarone weakly inhibited CYP2C9, CYP2D6, and CYP3A4-mediated activities with K i values of 45.1-271.6 mm. Desethylamiodarone competitively inhibited the catalytic activities of CYP2D6 (K i =4.5 mm) and noncompetitively inhibited CYP2A6 (K i =13.5 mm), CYP2B6 (K i =5.4 mm), and CYP3A4 (K i = 12.1 mm). The catalytic activities of CYP1A1 (K i =1.5 mm, a=5.7), CYP1A2 (K i =18.8 mm, a=2.6), CYP2C9 (K i =2.3 mm, a=5.9), and CYP2C19 (K i = 15.7 mm, a=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.

Inhibitory and Stimulative Effects of Amiodarone on Metabolism of Carvedilol in Human Liver Microsomes

“…According to previous reports, the concentration of CYP-specific inhibitors was determined as follows: 25 mM furafylline (inhibitor of CYP1A2), 10 mM sulfaphenazole (inhibitor of CYP2C9), 1 mM quinidine (inhibitor of CYP2D6), and 1 mM ketoconazole (inhibitor of CYP3A4). 9,10) The concentrations of amiodarone (50 mM) and desethylamiodarone (25 mM) were determined according to the report of Ohyama et al 13) In the pooled HLM (#18888), the oxidation activity for Rcarvedilol was significantly decreased by quinidine (to 49.7% of control), whereas that for S-carvedilol was decreased by furafylline (to 70.6% of control). The results reconfirmed that CYP2D6 and CYP1A2 in the pooled HLM contributed mainly to the oxidation of R-and S-carvedilol, respectively.…”

“…We evaluated the effect of amiodarone (50 mM), desethylamiodarone (25 mM), bilirubin (250 mM), hyodeoxycholic acid (250 mM), and zidovudine (1 mM) on the glucuronidation of carvedilol. [13][14][15] Assay of Carvedilol Enantiomers The amount of carvedilol in the samples was measured using chiral high performance liquid chromatography (HPLC) as described by Saito et al with minor modifications. [7][8][9][10]16) Briefly, carvedilol was extracted from the samples (0.1 ml) with 5 ml diethylether after alkalization in 3 ml of 0.1 M Britton-Robinson buffer (pH 8.5).…”

Single-Cell Analysis: Visualizing Pharmaceutical and Metabolite Uptake in Cells with Label-Free 3D Mass Spectrometry Imaging

“…Since the cell line does not metabolize amiodarone, the lung macrophages were doped with desethylamiodarone. 37,39 The metabolite has also been shown to accumulate in lung macrophages and contribute to the toxic effect of the drug. 40 The SIMS image shows the protonated molecule of the metabolite, [(C 23 H 25 I 2 NO 3 )+H] + , which was detected at m/z 618.0 (see Figure 4).…”

A frameshift variant of CYP2C8 was identified in a patient who suffered from rhabdomyolysis after administration of cerivastatin

“…This possibility could not be answered easily because the drug was withdrawn from the market. As CYP2C8 plays important roles in metabolizing therapeutic drugs such as paclitaxel, an anticancer drug (Rahman et al 1994); troglitazone, an antidiabetes drug ; and amiodarone, an antiarrhythmic drug (Ohyama et al 2000); attention should be paid when heterozygous subjects take those drugs.…”