Amiodarone

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Amiodarone
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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
Amiodarone.png


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 ? Compound Assessment
Adverse Events ?

Amiodarone causes abnormal liver function test results in 15-50% of patients. The spectrum of liver injury is wide, ranging from isolated asymptomatic transaminase elevations to a fulminant disorder. Hepatotoxicity is usually predictable, dose dependent, and has a direct hepatotoxic effect. Clinically important liver disease develops in less than 5% of patients. The pseudoalcoholic liver injury can range from steatosis, to alcoholic hepatitis-like neutrophilic infiltration and Mallory's hyaline, to cirrhosis. Rarely, an acute idiosyncratic hepatocellular injury resembling viral hepatitis or cholestatic hepatitis occurs. Hepatic granulomas have occasionally been observed.

Features that represent a direct effect of the drug on the liver and that are common to the majority of long-term recipients are ultrastructural phospholipidosis, unaccompanied by clinical liver disease. The cationic amphiphilic drug and its major metabolite desethylamiodarone accumulate in hepatocyte lysosomes and mitochondria and in bile duct epithelium.

Amiodarone has been shown to induce steatosis in both animal models and humans. Steatosis is a common, early histological finding of hepatic injury and is characterized by micro- and/or macrovesicular hepatocellular lipid accumulation. Although steatosis is reversible, it can lead to steatohepatitis involving hepatocellular necrosis and/or apoptosis.

Amiodarone’s toxicity seems to be generic with respect to cell type; and the limiting toxicity in humans is normally pulmonary, with adverse events observed in 5% of patients. Asymptomatic "foamy cell" phospholipidosis is common, but acute and chronic life-threatening epithelial cell apoptosis with fibrosis and inflammatory responses are observed with significant frequency.

References:

-Medscape Drug-Induced Hepatotoxicity Specific Agents and Their Effects on the Liver
-Harrison's Principles of Internal Medicine, 17e, Chapter 299. Toxic and Drug-Induced Hepatitis
-Spyros A. Papiris, Christina Triantafillidou, Likurgos Kolilekas, Despoina Markoulaki, and Effrosyni D. Manali, "Amiodarone: Review of Pulmonary Effects and Toxicity", Drug Saf 2010; 33 (7): 539-558.

Toxicity Mechanisms ? As a cationic ampiphilic compound, amiodarone causes phospholipidosis, with accumulation of lamellar bodies in lipid-rich organs such as lung and liver.

Amiodarone positions in the hydrophobic core of the lipid bilayer where it alters lipid dynamics and modulates the activity of membrane-bound proteins. This is believed to be the basis of its pharmacological activity (affecting ion transport} as well as its toxicity: inhibition of electron transport in oxidative phosphorylation plus inhibition of fatty acid β-oxidation, which causes steatosis. The effect on mitochondrial membrane potential is biphasic, with increased potential at low dose and decreased potential at high dose, implying multiple points of interaction.

References:

-Nora Andersona and Juergen Borlak, “Drug-induced phospholipidosis”, FEBS Letters 580 (2006) 5533–5540.
-Kodavanti, U.P. and Mehendale, H.M. (1990) “Cationic amphiphilic drugs and phospholipid storage disorder”, Pharmacol. Rev. 42, 327–354.
-M. Teresa Donato, Alicia Martínez-Romero, Nuria Jiménez, Alejandro Negro, Guadalupe Herrer, José V. Castell, José-Enrique O’Connor, M. José Gómez-Lechón, "Cytometric analysis for drug-induced steatosis in HepG2 cells.", Chemico-Biological Interactions 181 (2009) 417–423.
-Spyros A. Papiris, Christina Triantafillidou, Likurgos Kolilekas, Despoina Markoulaki, and Effrosyni D. Manali, "Amiodarone: Review of Pulmonary Effects and Toxicity", Drug Saf 2010; 33 (7): 539-558.
-I. Grattagliano et al. Biochemical mechanisms in drug-induced liver injury: Certainties and doubts World J Gastroenterol. 2009 October 21; 15(39): 4865–4876.
-Spaniol M. et al. Toxicity of amiodarone and amiodarone analogues on isolated rat liver mitochondria. J Hepatol. 2001 Nov; 35(5):628-36.
-Fromenty B. et al. Dual effect of amiodarone on mitochondrial respiration. Initial protonophoric uncoupling effect followed by inhibition of the respiratory chain at the levels of complex I and complex II. (1990) J Pharmacol Exp Ther 255:1377–1384.
-Fromenty B et al. Amiodarone inhibits the mitochondrial b-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice. (1990) J Pharmacol Exp Ther 255:1371–1376.
-Fromenty B. et al. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. (1995) Pharmacol Ther 67:101–154.
-K.M. Waldhauser et al. Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives The Journal of Pharmacology and Experimental Therapeutics 2006 Vol. 319, No. 3.

Therapeutic Target ? The antiarrhythmic effect of Amiodarone is due to at least two major properties: a prolongation of the myocardial cell action potential duration and refractory period (potassium channel inhibition) and noncompetitive α- and β-adrenergic inhibition.

References:

-Drugs.com: Amiodarone
-K.M. Waldhauser et al. Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives The Journal of Pharmacology and Experimental Therapeutics 2006 Vol. 319, No. 3.
-Singh BN (1996) Antiarrhythmic actions of amiodarone: a profile of a paradoxical agent. Am J Cardiol 78:41–53.

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
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.

SMILES CCCCC1=C(C2=CC=CC=C2O1)C(=O)C3=CC(=C(C(=C3)I)OCCN(CC)CC)I
InChI

InChI=1S/C25H29I2NO3/c1-4-7-11-22-23(18-10-8-9-12-21(18)31-22)24(29)17-15-19(26)25(20(27)16-17)30-14-13-28(5-2)6-3/h8-10,12,15-16H,4-7,11,13-14H2,1-3H3

InChI-Key

IYIKLHRQXLHMJQ-UHFFFAOYSA-N

Summary Hepatotoxic Effects from the LIINTOP FP6 Program
Hepatocellular necrosis.gif Apoptosis.gif Transporter inhibition.gif Cholestatic.gif Steatotic.gif Phospholipidosis.gif Hepatocyte function.gif Mithochondria impairment.gif Oxidative stress.gif DNA synthesis genotoxicity.gif Covalent binding.gif Idiosyncrasia metabolic.gif Idiosyncrasia immune.gif Bioactivation required.gif LIINTOP severity.gif 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

  1. 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.
  2. 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.
  3. Fromenty, B., Pessayre, D., 1995. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101–154.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. Halliwell, W.H., 1997. Cationic amphiphilic drug-induced phospholipidosis. Toxicol. Pathol. 25, 53–60.
  11. 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.
  12. 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.
  13. Nonoyama, T., Fukuda, R., 2008. Drug-induced phospholipidosis – pathological aspects and its prediction. J. Toxicol. Pathol. 21, 9–34.
  14. 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.
  15. Reasor, M.J., Hastings, K.L., Ulrich, R.G., 2006. Drug-induced phospholipidosis: issues and future directions. Expert Opin. Drug Saf. 5, 567–583.
  16. Reasor, M.J., Kacew, S., 2001. Drug-induced phospholipidosis: are there functional consequences? Exp. Biol. Med. (Maywood) 226, 825–830.
  17. 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.
  18. 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.
  19. Johannsen, D.L., Ravussin, E., 2009. The role of mitochondria in health and disease. Curr. Opin. Pharmacol. 9, 780–786.
  20. 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.
  21. 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.
  22. Masubuchi, Y., 2006. Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab. Pharmacokinet. 21, 347–356.
  23. Bradbury, M.W., Berk, P.D., 2004. Lipid metabolism in hepatic steatosis. Clin. Liver Dis. 8, 639–671 (xi).
  24. 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.
  25. 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.
  26. Fromenty, B., Pessayre, D., 1995. Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity. Pharmacol. Ther. 67, 101–154.
  27. 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.
  28. 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.
  29. 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.


PK-ADME ? Compound Assessment
PK parameters ? Maximum plasma concentrations are attained 3 to 7 hours after a single dose.

Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day.

Amiodarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen.

Following single dose administration in 12 healthy subjects, amiodarone exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite DEA.

References:

-WikiDoc: Amiodarone Pharmacokinetics and Molecular Data
-Vijaya Jaiswal et al. | Comparative bioavailability study with two amiodarone tablet formulations in healthy subjects, Int. J. Res. Pharm. Sci. Vol-1, Issue-4, 481-485, 2010.
-Riva E. et al Pharmacokinetics of amiodarone in man. J Cardiovasc Pharmacol. 1982 Mar-Apr;4(2):264-9.
-Xu Meng et al. Bioavailability of amiodarone tablets administered with and without food in healthy subjects The American Journal of Cardiology Volume 87, Issue 4, 15 February 2001, Pages 432-435.

Therapeutic window ? Therapeutic range 1.0 - 2.5 mg/L.

Arrhythmias recurred in 47% of patients with serum amiodarone concentrations of less than 1.0 mg/L, The risk of developing adverse reactions was related to serum amiodarone concentrations. Adverse reactions were common in patients with serum values exceeding 2.5 mg/L,

References:

-Rotmensch HH, et al. Steady-state serum amiodarone concentrations: relationships with antiarrhythmic efficacy and toxicity. Ann Intern Med. 1984 Oct; 101(4):462-9.

Metabolically activated ? Amiodarone is extensively metabolized in the liver via CYP2C8. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties.

No therapeutic range is established for DEA; activity and serum concentration are similar to parent drug.

References:

-Katri Maria Waldhauser, Michael Torok, Huy-Riem Ha, Urs Thomet, Daniel Konrad, Karin Brecht, Ferenc Follath, and Stephan Krahenbuhl, "Hepatocellular Toxicity and Pharmacological Effect of Amiodarone and Amiodarone Derivatives", JPET 319:1413–1423, 2006.
-Medscape: Pharmacokinetics and Metabolism N-Desethylamiodarone (hydrochloride) Cayman Chemical Item Number 9000537 Purity > 95% 10mg = 88$

Omics and IC50 Data ? Compound Assessment
Gene expression profiles known. ? References:
-HepaRG cells: Induction of Vesicular Steatosis by Amiodarone and Tetracycline Is Associated with Up-regulation of Lipogenic Genes in HepaRG Cells S. Antherieu et al. Hepatology 2011;53:1895-1905

References:

-Mice Disruption of Hepatic Lipid Homeostasis in Mice after Amiodarone Treatment Is Associated with Peroxisome Proliferator-Activated Receptor-alpha Target Gene Activation Tanya C. et al. The Journal of Pharmacology and Experimental Therapeutics Vol. 311, No. 3

Proteomics profiles known. ? References:
-HepaG2: Anke Van Summeren et al. Proteomics Investigations of Drug-Induced Hepatotoxicity in HepG2 Cells Toxicol. Sci. (2011) 120 (1): 109-122.
Metabonomics profiles known. ? References:
-Huy Riem Ha et al. Identification and quantitation of novel metabolites of amiodarone in plasma of treated patients European Journal of Pharmaceutical Sciences Volume 24, Issue 4, March 2005, Pages 271-279

References:

-Mina Hasegawa et al. Urinary metabolic fingerprinting for amiodarone-induced phospholipidosis in rats using FT-ICR MS, Experimental and Toxicologic Pathology Volume 59, Issue 2, 17 October 2007, Pages 115-120

Fluxomics profiles known. ?
Epigenomics profiles known. ?
Observed IC50 for in vitro cellular efficacy. ? Amiodarone is a sodium channel blocker. Amiodarone inhibited [3H]BTXB binding in a dose-dependent fashion, with an estimated IC50 value of 3.6 microM. This IC50 value is similar to reported clinically effective serum concentrations of amiodarone RS Sheldon et al. Amiodarone: biochemical evidence for binding to a receptor for class I drugs associated with the rat cardiac sodium channel.

References:

-Circulation Research. 1989;65:477-482

Amiodarone inhibited the activated muscarinic acetylcholine receptor-operated K+ current (role in the repolarization of atrial action potential) with IC50 values around 2 microM (Y Watanabe et al.). Inhibitory effect of amiodarone on the muscarinic acetylcholine receptor-operated potassium current in guinea pig atrial cells.

References:

-PET November 1996 vol. 279 no. 2 617-624.

Observed IC50 for in vitro cellular toxicity studies. ? HepG2 cells:


12 uM MEC – increased mitochondrial membrane potential
25 uM MEC – lipid accumulation
35 uM MEC – ROS accumulation
200 uM MEC – decreased mitochondrial membrane potential and GSH levels
75 - 105 uM IC50 - cell death

hESC-derived cardiomyocytes:
0.5 uM IC50 – cell death

Bovine pulmonary artery endothelial cells:
2 uM MEC - phoshpolipid accumulation (at 4 hours)
20 uM IC50 - cell death

References:

-W. J. MARTIN II, and D. M. HOWARD, "In Vitro Evidence for the Direct Toxicity of the Drug", Am J Pathol 1985, 120:344-350.
-Elizabeth Roquemore, Rahman Ismail, Sharon Davies, Catherine Hather, Elizabeth Price, Alexander Harrison, P J Kemp, N D Allen, and Stephen Minger (2011). Poster Download.
-Golli-Bennour EE et al. Cytotoxicity effects of amiodarone on cultured cells. Exp Toxicol Patho (2010), doi:10.1016/j.etp.2010.10.008
-M. Teresa Donato, Alicia Martínez-Romero, Nuria Jiménez, Alejandro Negro, Guadalupe Herrer, José V. Castell, José-Enrique O’Connor, M. José Gómez-Lechón, "Cytometric analysis for drug-induced steatosis in HepG2 cells.", Chemico-Biological Interactions 181 (2009) 417–423.
-Jinghai J. Xu, Peter V. Henstock, Margaret C. Dunn, Arthur R. Smith, Jeffrey R. Chabot, and David de Graaf, "Cellular Imaging Predictions of Clinical Drug-Induced Liver In",TOXICOLOGICAL SCIENCES 105(1), 97–105 (2008).

Physical Properties ? Compound Assessment
Accepted and listed within the ToxCast/Tox21 program. ? Yes - Included in ToxCast Phase I and II Chemicals List.
Substance stability. ?
Soluble in buffer solution at 30 times the in vitro IC50 for toxicity. ? Amiodarone water solubility: 0.07164 g/100ml (25°C) at pH 6.5, solubility was not substantially affected at pH range of 1.5-7.5 in aqueous solutions. (Bonati M, Gaspari F, D'Aranno V, Benfenati E, Neyroz P, Galletti F, Tognoni G. Physicochemical and analytical characteristics of amiodarone.J Pharm Sci. 1984; 73(6):829-31).

Amiodarone estimated intrinsic solubility : 1.5085E-05 mg/ml
Amiodarone estimated solubility in pure water at pH 7.5: 1.071E-03 mg/ml
Amiodarone estimated solubility in water at pH 7.4: 1.33E-03 mg/ml
(Calculations performed using ACD/PhysChem v 9.14)

Solubility as a function of pH and other parameters available on the wiki.

Amiodarone hydrochloride 50 mg/ml Sigma Aldrich A8423 Technical specification.

Solubility in DMSO 100 times buffer solubility. ? Amiodarone hydrochloride soluble to 50 mM in DMSO Tocris Bioscience
Vessel binding properties. ? Sorption of amiodarone to flexible PVC containers. [Weir SJ, Myers VA, Bengtson KD, Ueda CT. Sorption of amiodarone to polyvinyl chloride infusion bags and administration sets. Am J Hosp Pharm 1985; 42(12):2679-83].
Vapor pressure. (Non-volatile) ? Estimated vapor pressure: 6.56E-05 mmHg (Calculation performed using EPI Suite v4.10)

Calculated/Predicted Properties

Water Solubility Results
pH Sol,mg/ml 28+ 0 Graph
2 1.90e-2 100 - Amiodarone solubility.png
5.5 1.63e-2 100 -
6.5 7.08e-3 99.9 0.1
7.4 1.33e-3 98.9 1.1
10 1.86e-5 19.1 80.9
Summary Solubility Data
Intrinsic Solubility,mg/ml 1.5085e-5
Intrinsic Solubility,log(S,mol/l) -7.6312
Solubility in Pure Water at pH = 7.5,mg/ml 1.071e-3
Calculations performed using ACD/PhysChem v 9.14
LogD Results
pH LogD Graph
2 5.79 Amiodarone logd.png
5.5 5.86
6.5 6.22
7.4 6.94
10 8.8
Calculations performed using ACD/PhysChem v 9.14
Single-valued Properties
Property Value Units Error
LogP 8.89 1.04
MW 645.31 -
PSA 42.68 -
FRB 11 -
HDonors 0 -
HAcceptors 4 -
Rule Of 5 2 -
Molar Refractivity 144.38 cm3 0.3
Molar Volume 408.22 cm3 3
Parachor 1073.38 cm3 4
Index of Refraction 1.63 0.02
Surface Tension 47.8 dyne/cm 3
Density 1.58 g/cm3 0.06
Polarizability 57.24 10e-24 cm3 0.5
Calculations performed using ACD/PhysChem v 9.14
Property Name Value Units Source
pKa 8.72 SPARC v4.5
Estimated VP 6.56E-05 mm Hg EPI Suite v4.10
Estimated VP 0.008746 Pa EPI Suite v4.10
Estimated Water Solubility 5295 mg/L EPI Suite v4.10
WATERNT Frag Water Solubility Estimate 11196 mg/L EPI Suite v4.10
pKa Results
Acidic/Basic Acidic/Basic Aparrent pKa Value Error
28 MB 9.37 0.25
A = Acidic
B = Basic
MA = Most Acidic
MB = Most Basic
Calculations performed using ACD/PhysChem v 9.14

Authors of this ToxBank wiki page

David Bower, Egon Willighagen, Matthew Clark
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