Banner
Identification
Name Digitoxin
Accession Number DB01396
Type small molecule
Groups approved
Description

A cardiac glycoside sometimes used in place of digoxin. It has a longer half-life than digoxin; toxic effects, which are similar to those of digoxin, are longer lasting. (From Martindale, The Extra Pharmacopoeia, 30th ed, p665)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
Digitoksin
Digitoxinum
Digitoxoside
Salts Not Available
Brand names
Name Company
Crystodigin
Tardigal
Brand mixtures Not Available
Categories
  • Enzyme Inhibitors
  • Antiarrhythmic Agents
  • Cardiotonic Agents
  • Anti-Arrhythmia Agents
CAS number 71-63-6
Weight Average: 764.9391
Monoisotopic: 764.434692134
Chemical Formula C41H64O13
InChI Key InChIKey=WDJUZGPOPHTGOT-XUDUSOBPSA-N
InChI
InChI=1S/C41H64O13/c1-20-36(46)29(42)16-34(49-20)53-38-22(3)51-35(18-31(38)44)54-37-21(2)50-33(17-30(37)43)52-25-8-11-39(4)24(15-25)6-7-28-27(39)9-12-40(5)26(10-13-41(28,40)47)23-14-32(45)48-19-23/h14,20-22,24-31,33-38,42-44,46-47H,6-13,15-19H2,1-5H3/t20-,21-,22-,24-,25+,26-,27+,28-,29+,30+,31+,33+,34+,35+,36-,37-,38-,39+,40-,41+/m1/s1
Plain Text
IUPAC Name
4-[(1S,2S,5S,7R,10R,11S,14R,15R)-5-{[(2R,4S,5S,6R)-5-{[(2S,4S,5S,6R)-5-{[(2S,4S,5S,6R)-4,5-dihydroxy-6-methyloxan-2-yl]oxy}-4-hydroxy-6-methyloxan-2-yl]oxy}-4-hydroxy-6-methyloxan-2-yl]oxy}-11-hydroxy-2,15-dimethyltetracyclo[8.7.0.0^{2,7}.0^{11,15}]heptadecan-14-yl]-2,5-dihydrofuran-2-one
SMILES
[H][C@]12CC[C@]3([H])[C@]([H])(CC[C@]4(C)[C@H](CC[C@]34O)C3=CC(=O)OC3)[C@@]1(C)CC[C@@H](C2)O[C@H]1C[C@H](O)[C@H](O[C@H]2C[C@H](O)[C@H](O[C@H]3C[C@H](O)[C@H](O)[C@@H](C)O3)[C@@H](C)O2)[C@@H](C)O1
Plain Text
Mass Spec show (12.6 KB)
Taxonomy
Kingdom Not Available
Classes
  • Steroids and Steroid Derivatives
Substructures
  • Steroids and Steroid Derivatives
  • Carboxylic Acids and Derivatives
  • Glycerol and Derivatives
  • Hydroxy Compounds
  • Alkanes and Alkenes
  • Pyrans
  • Acetates
  • Acetals and Derivatives
  • Sterols
  • Lactones
  • Ethers
  • Bicyclohexanes
  • Alcohols and Polyols
  • Heterocyclic compounds
Pharmacology
Indication For the treatment and management of congestive cardiac insufficiency, arrhythmias and heart failure.
Pharmacodynamics Digitoxin is a cardiac glycoside sometimes used in place of DIGOXIN. It has a longer half-life than digoxin; toxic effects, which are similar to those of digoxin, are longer lasting (From Martindale, The Extra Pharmacopoeia, 30th ed, p665). Unlike digoxin (which is eliminated from the body via the kidneys), it is eliminated via the liver, so could be used in patients with poor or erratic kidney function. However, it is now rarely used in current UK medical practice. While there have been several controlled trials which have shown digoxin to be effective in a proportion of patients treated for heart failure, there is not the same strong evidence base for digitoxin, although it is presumed to be similarly effective.
Mechanism of action Digitoxin inhibits the Na-K-ATPase membrane pump, resulting in an increase in intracellular sodium and calcium concentrations. Increased intracellular concentrations of calcium may promote activation of contractile proteins (e.g., actin, myosin). Digitoxin also acts on the electrical activity of the heart, increasing the slope of phase 4 depolarization, shortening the action potential duration, and decreasing the maximal diastolic potential.
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism Hepatic.
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity Digitoxin exhibits similar toxic effects to the more-commonly used digoxin, namely: anorexia, nausea, vomiting, diarrhoea, confusion, visual disturbances, and cardiac arrhythmias.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
Packagers
Dosage forms
Form Route Strength
Liquid Oral
Liquid Oral
Prices
Unit description Cost Unit
Digitoxin powder 486.85 USD g
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents Not Available
Properties
State solid
Experimental Properties
Property Value Source
melting point 255.5 °C PhysProp
water solubility 3.9 mg/L (at 25 °C) YALKOWSKY,SH & DANNENFELSER,RM (1992)
logP 1.85 SANGSTER (1993)
Predicted Properties
Property Value Source
water solubility 2.89e-02 g/l ALOGPS
logP 2.33 ALOGPS
logP 3.6 ChemAxon
logS -4.4 ALOGPS
pKa (strongest acidic) 7.18 ChemAxon
pKa (strongest basic) 0.24 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 12 ChemAxon
hydrogen donor count 5 ChemAxon
polar surface area 182.83 ChemAxon
rotatable bond count 7 ChemAxon
refractivity 191.72 ChemAxon
polarizability 83.58 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Belz GG, Breithaupt-Grogler K, Osowski U: Treatment of congestive heart failure—current status of use of digitoxin. Eur J Clin Invest. 2001;31 Suppl 2:10-7. Pubmed
  2. Kurowski V, Iven H, Djonlagic H: Treatment of a patient with severe digitoxin intoxication by Fab fragments of anti-digitalis antibodies. Intensive Care Med. 1992;18(7):439-42. Pubmed
  3. Johansson S, Lindholm P, Gullbo J, Larsson R, Bohlin L, Claeson P: Cytotoxicity of digitoxin and related cardiac glycosides in human tumor cells. Anticancer Drugs. 2001 Jun;12(5):475-83. Pubmed
  4. Hippius M, Humaid B, Sicker T, Hoffmann A, Gottler M, Hasford J: Adverse drug reaction monitoring—digitoxin overdosage in the elderly. Int J Clin Pharmacol Ther. 2001 Aug;39(8):336-43. Pubmed
External Links
Resource Link
KEGG Drug D00297 Link_out
KEGG Compound C06955 Link_out
PubChem Compound 441207 Link_out
PubChem Substance 46506035 Link_out
ChemSpider 389987 Link_out
ChEBI 28544 Link_out
ChEMBL 28544 Link_out
Therapeutic Targets Database DAP000120 Link_out
PharmGKB PA449316 Link_out
Drug Product Database 2236621 Link_out
Wikipedia http://en.wikipedia.org/wiki/Digitoxin Link_out
ATC Codes
  • C01AA01
  • C01AA04
AHFS Codes
  • 92:02.00*
PDB Entries Not Available
FDA label Not Available
MSDS show (73.4 KB)
Interactions
Drug Interactions
Drug Interaction
Bendroflumethiazide Possible electrolyte variations and arrhythmias
Bumetanide Possible electrolyte variations and arrhythmias
Chlorthalidone Possible electrolyte variations and arrhythmias
Ethacrynic acid Possible electrolyte variations and arrhythmias
Furosemide Possible electrolyte variations and arrhythmias
Hydrochlorothiazide Possible electrolyte variations and arrhythmias
Indapamide Possible electrolyte variations and arrhythmias
Metolazone Possible electrolyte variations and arrhythmias
Quinidine Quinine/quinidine increases the effect of digoxin
Quinine Quinine/quinidine increases the effect of digoxin
Telithromycin Telithromycin may reduce clearance of Digitoxin. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Digitoxin if Telithromycin is initiated, discontinued or dose changed.
Verapamil Verapamil may increase the serum concentration of Digitoxin by decreasing its metabolism and clearance. Monitor for changes in the therapeutic/adverse effects of Digitoxin if Verpamail is initiated, discontinued or dose changed.
Voriconazole Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of digitoxin by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of digitoxin if voriconazole is initiated, discontinued or dose changed.
Food Interactions
  • Avoid avocado.
  • Avoid bran and high fiber foods within 2 hours of taking this medication.
  • Avoid excess salt/sodium unless otherwise instructed by your physician.
  • Avoid milk, calcium containing dairy products, iron, antacids, or aluminum salts 2 hours before or 6 hours after using antacids while on this medication.
  • Avoid salt substitutes containing potassium.
  • Limit garlic, ginger, gingko, and horse chestnut.
Targets

1. Sodium/potassium-transporting ATPase alpha-1 chain

Pharmacological action: yes
Actions: inhibitor

This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. This action creates the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients

Organism class: human
UniProt ID: P05023 Link_out
Gene: ATP1A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen JJ, Wang PS, Chien EJ, Wang SW: Direct inhibitory effect of digitalis on progesterone release from rat granulosa cells. Br J Pharmacol. 2001 Apr;132(8):1761-8. Pubmed
  2. Marcus FI, Ryan JN, Stafford MG: The reactivity of derivatives of digoxin and digitoxin as measured by the Na-K-atpase displacement assay and by radioimmunoassay. J Lab Clin Med. 1975 Apr;85(4):610-20. Pubmed
  3. Prignitz R, Frohlich D, Hoffmeister G: [Influence of roentgen rays on electrolyte changes and metabolism of the myocardium. VII. Radiation-induced inhibition of the sodium- and potassium—activated microscomal-trasport ATPase] Strahlentherapie. 1976 Apr;151(4):356-65. Pubmed
  4. Bluschke V, Bonn R, Greeff K: Increase in the (Na+ + K+)-ATPase activity in heart muscle after chronic treatment with digitoxin or potassium deficient diet. Eur J Pharmacol. 1976 May;37(1):189-91. Pubmed
  5. Fricke U: [New aspects on the mode of action of cardiac glycosides] Fortschr Med. 1976 Nov 11;94(32):1037-45. Pubmed
  6. Hauck C, Potter T, Bartz M, Wittwer T, Wahlers T, Mehlhorn U, Scheiner-Bobis G, McDonough AA, Bloch W, Schwinger RH, Muller-Ehmsen J: Isoform specificity of cardiac glycosides binding to human Na+,K+-ATPase alpha1beta1, alpha2beta1 and alpha3beta1. Eur J Pharmacol. 2009 Nov 10;622(1-3):7-14. Epub 2009 Sep 12. Pubmed
Enzymes

1. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

2. Cholesterol side-chain cleavage enzyme, mitochondrial

Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone

UniProt ID: P05108 Link_out
Gene: CYP11A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Wang SW, Lin H, Hwang JJ, Wang PS: Inhibition of testosterone secretion by digitoxin in rat testicular interstitial cells. J Cell Biochem. 1999 Jul 1;74(1):74-80. Pubmed
Transporters

1. Solute carrier organic anion transporter family member 1A2

Actions: inhibitor

Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity)

UniProt ID: P46721 Link_out
Gene: SLCO1A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Bossuyt X, Muller M, Hagenbuch B, Meier PJ: Polyspecific drug and steroid clearance by an organic anion transporter of mammalian liver. J Pharmacol Exp Ther. 1996 Mar;276(3):891-6. Pubmed

2. Solute carrier organic anion transporter family member 4C1

Actions: inhibitor

Organic anion transporter, capable of transporting pharmacological substances such as digoxin, ouabain, thyroxine, methotrexate and cAMP. May participate in the regulation of membrane transport of ouabain. Involved in the uptake of the dipeptidyl peptidase-4 inhibitor sitagliptin and hence may play a role in its transport into and out of renal proximal tubule cells. May be involved in the first step of the transport pathway of digoxin and various compounds into the urine in the kidney. May be involved in sperm maturation by enabling directed movement of organic anions and compounds within or between cells. This ion- transporting process is important to maintain the strict epididymal homeostasis necessary for sperm maturation. May have a role in secretory functions since seminal vesicle epithelial cells are assumed to secrete proteins involved in decapacitation by modifying surface proteins to facilitate the acquisition of the ability to fertilize the egg

UniProt ID: Q6ZQN7 Link_out
Gene: SLCO4C1 Link_out
Protein Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Mikkaichi T, Suzuki T, Onogawa T, Tanemoto M, Mizutamari H, Okada M, Chaki T, Masuda S, Tokui T, Eto N, Abe M, Satoh F, Unno M, Hishinuma T, Inui K, Ito S, Goto J, Abe T: Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3569-74. Epub 2004 Mar 1. Pubmed

3. Multidrug resistance protein 1

Actions: substrate

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Pauli-Magnus C, Murdter T, Godel A, Mettang T, Eichelbaum M, Klotz U, Fromm MF: P-glycoprotein-mediated transport of digitoxin, alpha-methyldigoxin and beta-acetyldigoxin. Naunyn Schmiedebergs Arch Pharmacol. 2001 Mar;363(3):337-43. Pubmed
Carriers

1. Serum albumin

Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood

UniProt ID: P02768 Link_out
Gene: ALB Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Hage DS, Sengupta A: Characterisation of the binding of digitoxin and acetyldigitoxin to human serum albumin by high-performance affinity chromatography. J Chromatogr B Biomed Sci Appl. 1999 Mar 5;724(1):91-100. Pubmed
  2. Dasgupta A, Vega AE, Wells A, Datta P: Sensitive methods for determination of free digitoxin concentration using digitoxin immunoassays: demonstration of elevated free digitoxin concentration caused by digitoxin-phenytoin interaction by applying these new techniques. Ther Drug Monit. 1999 Dec;21(6):625-30. Pubmed
  3. Datta P, Dasgupta A: Interactions between drugs and Asian medicine: displacement of digitoxin from protein binding site by bufalin, the constituent of Chinese medicines Chan Su and Lu-Shen-Wan. Ther Drug Monit. 2000 Apr;22(2):155-9. Pubmed
  4. Dasgupta A, Paul A, Wells A: Uremic sera contain inhibitors that block digitoxin-valproic acid interaction. Am J Med Sci. 2001 Oct;322(4):204-8. Pubmed
Comments
Drug created on July 08, 2007 11:03 / Updated on February 08, 2013 16:20