Amiodarone
From ToxBankWiki
Executive Summary
Compound | Amiodarone |
Toxicities | Steatosis, phospholipidosis, cytotoxicity. |
Mechanisms | Amiodarone inhibits mitochondrial fatty oxidation and oxidative phosphorylation. As a cationic, amphiphilic drug, it also induces phospholipidosis. Toxicity does not require metabolic activation and is observed in multiple organs and cell types. |
Comments | Amiodarone was selected as a standard for promiscuous activities associated with membrane disruption. |
Feedback Contact | Gold Compound Working Group (GCWG) |
Amiodarone | |
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Identifiers | |
Leadscope Id | LS-87088 |
CAS | 1951-25-3 |
DrugBank | APRD00288 |
ChemSpider | 2072 |
UNII | N3RQ532IUT |
Pathway DBs | |
KEGG | D02910 |
Assay DBs | |
PubChem CID | 2157 |
ChEMBL | 633 |
Omics DBs | |
Open TG-Gate | 00033 |
Properties | |
pKa | 8.72 |
ToxCast Accepted | yes |
Toxic Effect | Steatosis |
ToxBank Accepted | yes |
Approved on | 2011-06-28 |
Target | beta blocker, K channel blocker |
Toxicities | Cytotoxicity,Phospholipidosis,Steatosis |
- In Vivo Data
- LIINTOP Data
- PK-ADME Data
- 'Omics and IC50 Data
- Physical Properties
- Recommended Product and Source
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Human Adverse Events
The following data table has been mined from the Adverse Events Reporting System (AERS) of the US FDA. Significant human liver events. The first column ("# Reports") is the number of reports found for the corresponding adverse event reported in the third column ("Adverse Event"). The second column ("Report:Baseline Ratio") is ratio calculated from the number of reports ("# Reports") divided by a calculated expected statistical baseline number of reports.
# Reports | Report:Baseline Ratio | Adverse Event |
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3 | 9.62555 | biliary cirrhosis |
1 | 6.83103 | cholestatic liver injury |
12 | 4.84951 | coma hepatic |
37 | 3.19478 | hepatic cirrhosis |
23 | 3.26991 | hepatitis acute |
5 | 3.30362 | hepatocellular injury |
41 | 3.16351 | hepatotoxicity |
6 | 3.60446 | ischaemic hepatitis |
2 | 21.1762 | malignant neoplasm of ampulla of vater |
1 | 22.2907 | oedema due to hepatic disease |
FDA and Label Information
The following link will display all of the currently approved FDA drug products on the market. The web page will contain a table listing all current products by their respective Tradenames and primary active ingredients. The list is navigable by simply clicking on the product of interest, which will in turn list all of the NDA's and ANDA's associated with that product. From here users can click on a specific NDA or ANDA and see documents that have been submitted for the product that the FDA has made available via their website. The types of documents include approval history, letters, reviews and labels.
FDA Approved Products
This next url will perform a search in the FDA's system for all labels for products that contain "Amiodarone" as an active ingredient.
FDA Label Search
PubMed references
The following resource link will perform a PubMed query for the terms "Amiodarone" and "liver toxicity".
Amiodarone Search
The table listed below contains a summarized listing of toxic effect information leveraged from the 6th European Framework Programme project LIINTOP. For a complete listing of the Gold Compound evaluation criteria please see the Gold Compound Evaluation and Comments immediately following the summary table below.
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Summary Hepatotoxic Effects from the LIINTOP FP6 Program | |||||||||||||||||||||
References | |||||||||||||||||||||
+ | + | + | 3 |
[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] |
References
- ↑ Chariot, P., Drogou, I., de Lacroix-Szmania, I., Eliezer-Vanerot, M.C., Chazaud, B., Lombes, A., Schaeffer, A., Zafrani, E.S., 1999. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J. Hepatol. 30, 156–160.
- ↑ Donato, M.T., Martinez-Romero, A., Jimenez, N., Negro, A., Herrera, G., Castell, J.V., O’Connor, J.E., Gomez-Lechon, M.J., 2009. Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem. Biol. Interact. 181, 417–423.
- ↑ Fromenty, B., Pessayre, D., 1995. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101–154.
- ↑ Fromenty, B., Pessayre, D., 1997. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. J. Hepatol. 26 (Suppl. 2), 43–53.
- ↑ Kasahara, T., Tomita, K., Murano, H., Harada, T., Tsubakimoto, K., Ogihara, T., Ohnishi, S., Kakinuma, C., 2006. Establishment of an in vitro high-throughput screening assay for detecting phospholipidosis-inducing potential. Toxicol. Sci. 90, 133–141.
- ↑ Letteron, P., Sutton, A., Mansouri, A., Fromenty, B., Pessayre, D., 2003. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 38, 133–140.
- ↑ Nioi, P., Perry, B.K., Wang, E.J., Gu, Y.Z., Snyder, R.D., 2007. In vitro detection of druginduced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol. Sci. 99, 162–173.
- ↑ Sawada, H., Takami, K., Asahi, S., 2005. A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol. Sci. 83, 282–292.
- ↑ Chatman, L.A., Morton, D., Johnson, T.O., Anway, S.D., 2009. A strategy for risk management of drug-induced phospholipidosis. Toxicol. Pathol. 37, 997–1005.
- ↑ Halliwell, W.H., 1997. Cationic amphiphilic drug-induced phospholipidosis. Toxicol. Pathol. 25, 53–60.
- ↑ Kasahara, T., Tomita, K., Murano, H., Harada, T., Tsubakimoto, K., Ogihara, T., Ohnishi, S., Kakinuma, C., 2006. Establishment of an in vitro high-throughput screening assay for detecting phospholipidosis-inducing potential. Toxicol. Sci. 90, 133–141.
- ↑ Nioi, P., Perry, B.K., Wang, E.J., Gu, Y.Z., Snyder, R.D., 2007. In vitro detection of druginduced phospholipidosis using gene expression and fluorescent phospholipid based methodologies. Toxicol. Sci. 99, 162–173.
- ↑ Nonoyama, T., Fukuda, R., 2008. Drug-induced phospholipidosis – pathological aspects and its prediction. J. Toxicol. Pathol. 21, 9–34.
- ↑ Pappu, A., Hostetler, K.Y., 1984. Effect of cationic amphiphilic drugs on the hydrolysis of acidic and neutral phospholipids by liver lysosomal phospholipase A. Biochem. Pharmacol. 33, 1639–1644.
- ↑ Reasor, M.J., Hastings, K.L., Ulrich, R.G., 2006. Drug-induced phospholipidosis: issues and future directions. Expert Opin. Drug Saf. 5, 567–583.
- ↑ Reasor, M.J., Kacew, S., 2001. Drug-induced phospholipidosis: are there functional consequences? Exp. Biol. Med. (Maywood) 226, 825–830.
- ↑ Sawada, H., Takami, K., Asahi, S., 2005. A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol. Sci. 83, 282–292.
- ↑ Hynes, J., Marroquin, L.D., Ogurtsov, V.I., Christiansen, K.N., Stevens, G.J., Papkovsky, D.B., Will, Y., 2006. Investigation of drug-induced mitochondrial toxicity using fluorescence-based oxygen-sensitive probes. Toxicol. Sci. 92, 186–200.
- ↑ Johannsen, D.L., Ravussin, E., 2009. The role of mitochondria in health and disease. Curr. Opin. Pharmacol. 9, 780–786.
- ↑ Jones, D.P., Lemasters, J.J., Han, D., Boelsterli, U.A., Kaplowitz, N., 2010. Mechanisms of pathogenesis in drug hepatotoxicity putting the stress on mitochondria. Mol. Interv. 10, 98–111.
- ↑ Labbe, G., Pessayre, D., Fromenty, B., 2008. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam. Clin. Pharmacol. 22, 335–353.
- ↑ Masubuchi, Y., 2006. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21, 347–356.
- ↑ Bradbury, M.W., Berk, P.D., 2004. Lipid metabolism in hepatic steatosis. Clin. Liver Dis. 8, 639–671 (xi).
- ↑ Chariot, P., Drogou, I., de Lacroix-Szmania, I., Eliezer-Vanerot, M.C., Chazaud, B., Lombes, A., Schaeffer, A., Zafrani, E.S., 1999. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J. Hepatol. 30, 156–160.
- ↑ Donato, M.T., Martinez-Romero, A., Jimenez, N., Negro, A., Herrera, G., Castell, J.V., O’Connor, J.E., Gomez-Lechon, M.J., 2009. Cytometric analysis for drug-induced steatosis in HepG2 cells. Chem. Biol. Interact. 181, 417–423.
- ↑ Fromenty, B., Pessayre, D., 1995. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101–154.
- ↑ Fromenty, B., Pessayre, D., 1997. Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines. J. Hepatol. 26 (Suppl. 2), 43–53.
- ↑ Letteron, P., Sutton, A., Mansouri, A., Fromenty, B., Pessayre, D., 2003. Inhibition of microsomal triglyceride transfer protein: another mechanism for drug-induced steatosis in mice. Hepatology 38, 133–140.
- ↑ Shokolenko, I., Venediktova, N., Bochkareva, A., Wilson, G.L., Alexeyev, M.F., 2009. Oxidative stress induces degradation of mitochondrial DNA. Nucleic Acids Res. 37, 2539–2548.
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Calculated/Predicted Properties
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