The inhibitory effect of amiodarone and desethylamiodarone on dextromethorphan <i>O</i>-demethylation in human and rat liver microsomes

Jaruratanasirikul, Sutep; Hortiwakul, Ratri

doi:10.1111/j.2042-7158.1994.tb05721.x

Cited by 7 publications

(5 citation statements)

References 17 publications

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“…The results in our inhibition study with amiodarone toward CYP2C9, CYP2D6, and CYP3A4 were similar to those of these previous studies, in terms of the weak inhibitory effects. It has been suggested that desethylamiodarone exhibited a stronger inhibition of CYP2D6 activity than did amiodarone [ 21]. In the present study, we showed that desethylamiodarone inhibit other CYP activities such as CYP1A1, CYP1A2, CYP2A6, CYP2B6, and CYP2C19 with more potent effects than amiodarone.…”

Section: Discussionsupporting

confidence: 61%

“…In another study [ 20], amiodarone was reported to inhibit phenytoin hydroxylation (CYP2C9) in human liver microsomes ( IC 50 =25 μm ), but not bufuralol hydroxylation (CYP2D6) and felodipine oxidation (CYP3A4) in human liver microsomes ( IC 50 >100 μm ). Furthermore, Jaruratanasirikul & Hortiwakul [ 21] reported that dextromethorphan O ‐demethylation (CYP2D6) was inhibited by amiodarone and desethylamiodarone with K i values of 52.7 μm and 34.4 μm, respectively. The results in our inhibition study with amiodarone toward CYP2C9, CYP2D6, and CYP3A4 were similar to those of these previous studies, in terms of the weak inhibitory effects.…”

Section: Discussionmentioning

confidence: 99%

“…These drugs are substrates of CYP2C9, CYP2D6, or CYP3A4 [ 19]. However, there have been few in vitro studies in which the inhibitory effects of amiodarone and desethylamiodarone on CYP activities were determined [ 7, 20, 21].…”

Section: Introductionmentioning

confidence: 99%

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

Ohyama

Nakajima

Suzuki

et al. 2000

Brit J Clinical Pharma

175

153

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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.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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

Ohyama

Nakajima

Suzuki

et al. 2000

Brit J Clinical Pharma

175

153

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“…O-Demethylation of Dextromethorphan-The O-demethylation of dextromethorphan was carried out essentially as described (27) in 100 mM phosphate, pH 7.4, containing 0.3 units of NADPH-cytochrome-P450 reductase, 5 g of third protein component or 5 g of fraction TM1 (Fig. 3), 40 M DLPC, and 3.3 mM MgCl 2 in a final volume of 300 l.…”

Section: Analytical Proceduresmentioning

confidence: 99%

Isolation and Characterization of the Protein Components of the Liver Microsomal O2-insensitive NADH-Benzamidoxime Reductase

Clement

Lomb

Möller

1997

Journal of Biological Chemistry

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Drugs containing strong basic nitrogen functional groups can be N-oxygenated to genotoxic products. While the reduction of such products is of considerable toxicological significance, most in vitro studies have focused on oxygen-sensitive reductase systems. However, an oxygen-insensitive microsomal hydroxylamine reductase consisting of NADH, cytochrome b 5 , its reductase, and a third unidentified protein component has been known for some time (Kadlubar, F. F., and Ziegler, D. M. (1974) Arch. Biochem. Biophys. 162, 83-92). This report describes the isolation and identification of all of the components required for the reconstitution of an oxygen-insensitive liver microsomal system capable of catalyzing the efficient reduction of primary N-hydroxylated structures such as amidines, guanidines, amidinohydrazones, and similar functional groups. In addition to cytochrome b 5 and its reductase, the reconstituted system requires phosphatidylcholine and a P450 isoenzyme that has been purified to homogeneity from pig liver. The participation of cytochrome b 5 and NADH cytochrome b 5 reductase in cytochrome P450-dependent biotransformations has previously only been described for oxidative processes. The data presented suggest that this system may be an important catalyst in the reduction of genotoxic N-hydroxylated nitrogen components in liver. Their facile reduction by cellular NADH may be the reason why N-hydroxylated products can be missed by studies in vivo. Furthermore, the enzyme system is involved in the reduction of amidoximes and similar functional groups, which can be used as prodrug functionalities for amidines and related groups.The metabolism of nitrogen-containing functional groups has become a topic of considerable interest since the early discovery that N-hydroxylated intermediates are often responsible for the toxic and/or carcinogenic properties of aromatic amines, hydrazines, and amides (1). On the other hand, the more facile N-oxygenation of secondary and tertiary alkylamines to hydroxylamines and N-oxides was considered as a route for detoxication (2, 3), and it was generally assumed that the strongly basic nitrogen compounds were metabolically stable. However, we have demonstrated that even the protonated hydrophilic amidines (4 -6), as well as diamidines such as pentamidine and diminazene and also guanidines and amidinohydrazones, are capable of undergoing metabolic N-oxygenation by liver microsomal cytochrome P450 monooxygenases (7,8). The N-oxygenation of these functional groups produces more reactive metabolites, and the genotoxic properties of benzamidoxime are well known (9). During investigations of the metabolic fate of strongly basic N-hydroxylated xenobiotics, we observed that they were readily reduced both in vivo and in vitro by a microsomal system present in all mammalian species (rats, rabbits, pigs, and humans) tested to date (10 -13).Preliminary experiments indicated that this system (10) had many of the characteristics of the microsomal O 2 -insensitive hydroxylamine reductase descri...

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“…For example, many different substrates were permitted, as were various types of inhibition, including competitive, partial competitive, mixed, and noncompetitive . This process yielded a relatively small but chemically diverse training set of 100 drugs, drug-like compounds, and naturally occurring chemicals, spanning molecular weights from 127 to 721, with K i values between 0.0048 μM and 1000 μM. ,− …”

Section: Introductionmentioning

confidence: 99%

Use of Robust Classification Techniques for the Prediction of Human Cytochrome P450 2D6 Inhibition

Susnow¹,

Dixon²

2003

J. Chem. Inf. Comput. Sci.

150

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A new in silico model is developed to predict cytochrome P450 2D6 inhibition from 2D chemical structure. Using a diverse training set of 100 compounds with published inhibition constants, an ensemble approach to recursive partitioning is applied to create a large number of classification trees, each of which yields a yes/no prediction about inhibition for a given compound. These binary classifications are combined to provide an overall prediction, which answers the yes/no question about inhibition and provides a measure of confidence about that prediction. Compared to single-tree models, the ensemble approach is less sensitive to noise in the experimental data as well as to changes in the training set. Internal validation tests indicated an overall classification accuracy of 75%, whereas predictions applied to an external set of 51 compounds yielded 80% accuracy, with all inhibitors correctly identified. The speed and 2D nature of this model make it appropriate for high-throughput processing of large chemical libraries, and the confidence level provides a continuous scale on which to prioritize compounds.

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The inhibitory effect of amiodarone and desethylamiodarone on dextromethorphan O-demethylation in human and rat liver microsomes

Cited by 7 publications

References 17 publications

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

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

Isolation and Characterization of the Protein Components of the Liver Microsomal O2-insensitive NADH-Benzamidoxime Reductase

Use of Robust Classification Techniques for the Prediction of Human Cytochrome P450 2D6 Inhibition

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