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

Similar Structures

Synonyms

Digitoksin
Digitoxin
Digitoxina
Digitoxine
Digitoxinum
Digitoxoside

External IDs

NSC-7529

Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Digitaline Welcker Tab 0.1mg	Tablet	.1 mg	Oral	Welcker Lyster Ltd., Division Of Technilab Inc.	1951-12-31	2001-09-05

International/Other Brands

Crystodigin / Tardigal

Categories

UNII

E90NZP2L9U

CAS number

71-63-6

Weight

Average: 764.9391
Monoisotopic: 764.434692134

Chemical Formula

C₄₁H₆₄O₁₃

InChI Key

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

IUPAC Name

4-[(1R,3aS,3bR,5aR,7S,9aS,9bS,11aR)-7-{[(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}-3a-hydroxy-9a,11a-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2,5-dihydrofuran-2-one

SMILES

[H][C@@]1(CC[C@]2(O)[C@]3([H])CC[C@]4([H])C[C@H](CC[C@]4(C)[C@@]3([H])CC[C@]12C)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)C1=CC(=O)OC1

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.

Target	Actions	Organism
ASodium/potassium-transporting ATPase subunit alpha-1	inhibitor	Humans

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

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

Drug	Interaction
(R)-warfarin	The metabolism of Digitoxin can be decreased when combined with (R)-warfarin.
(S)-Warfarin	The metabolism of Digitoxin can be decreased when combined with (S)-Warfarin.
1alpha-Hydroxyvitamin D5	The risk or severity of ventricular arrhythmias and Cardiac Arrhythmia can be increased when 1alpha-Hydroxyvitamin D5 is combined with Digitoxin.
3,5-diiodothyropropionic acid	The metabolism of Digitoxin can be decreased when combined with 3,5-diiodothyropropionic acid.
4-hydroxycoumarin	The metabolism of 4-hydroxycoumarin can be decreased when combined with Digitoxin.
5-androstenedione	The metabolism of Digitoxin can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide B	The metabolism of Digitoxin can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanine	The metabolism of Digitoxin can be decreased when combined with 6-O-benzylguanine.
7-ethyl-10-hydroxycamptothecin	The metabolism of Digitoxin can be decreased when combined with 7-ethyl-10-hydroxycamptothecin.
9-aminocamptothecin	The metabolism of Digitoxin can be decreased when combined with 9-aminocamptothecin.

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.

References

General References

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:11525233]
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:1469187]
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:11395576]
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:11515708]

External Links

Human Metabolome Database: HMDB0015468
KEGG Drug: D00297
KEGG Compound: C06955
PubChem Compound: 441207
PubChem Substance: 46506035
ChemSpider: 389987
BindingDB: 46356
ChEBI: 28544
ChEMBL: CHEMBL254219
Therapeutic Targets Database: DAP000120
PharmGKB: PA449316
Wikipedia: Digitoxin

ATC Codes

C01AA04 — Digitoxin

MSDS

Download (73.4 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
2	Completed	Treatment	Cystic Fibrosis (CF)	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Spectrum Pharmaceuticals

Dosage forms

Form	Route	Strength
Tablet	Oral	.1 mg

Prices

Unit description	Cost	Unit
Digitoxin powder	486.85USD	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 (°C)	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	0.0289 mg/mL	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 Å²	ChemAxon
Rotatable Bond Count	7	ChemAxon
Refractivity	191.72 m³·mol^-1	ChemAxon
Polarizability	83.54 Å³	ChemAxon
Number of Rings	8	ChemAxon
Bioavailability	0	ChemAxon
Rule of Five	No	ChemAxon
Ghose Filter	No	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	Yes	ChemAxon

Predicted ADMET features

Property	Value	Probability
Human Intestinal Absorption	+	0.9718
Blood Brain Barrier	-	0.557
Caco-2 permeable	-	0.8386
P-glycoprotein substrate	Substrate	0.8528
P-glycoprotein inhibitor I	Inhibitor	0.5557
P-glycoprotein inhibitor II	Non-inhibitor	0.6021
Renal organic cation transporter	Non-inhibitor	0.8473
CYP450 2C9 substrate	Non-substrate	0.8687
CYP450 2D6 substrate	Non-substrate	0.9116
CYP450 3A4 substrate	Substrate	0.7407
CYP450 1A2 substrate	Non-inhibitor	0.8902
CYP450 2C9 inhibitor	Non-inhibitor	0.9082
CYP450 2D6 inhibitor	Non-inhibitor	0.9412
CYP450 2C19 inhibitor	Non-inhibitor	0.9258
CYP450 3A4 inhibitor	Non-inhibitor	0.901
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9381
Ames test	Non AMES toxic	0.9233
Carcinogenicity	Non-carcinogens	0.9637
Biodegradation	Not ready biodegradable	0.9671
Rat acute toxicity	4.4764 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9812
hERG inhibition (predictor II)	Inhibitor	0.7759

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Download (12.6 KB)

Spectra

Spectrum	Spectrum Type	Splash Key
Mass Spectrum (Electron Ionization)	MS	splash10-052g-9620000000-5ddc0df4702d2f0b8581
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
13C NMR Spectrum	1D NMR	Not Applicable

Taxonomy

Description: This compound belongs to the class of organic compounds known as cardenolide glycosides and derivatives. These are compounds containing a carbohydrate glycosidically bound to the cardenolide moiety.
Kingdom: Organic compounds
Super Class: Lipids and lipid-like molecules
Class: Steroids and steroid derivatives
Sub Class: Steroid lactones
Direct Parent: Cardenolide glycosides and derivatives
Alternative Parents: Steroidal glycosides / Oligosaccharides / 14-hydroxysteroids / O-glycosyl compounds / Oxanes / Butenolides / Tertiary alcohols / Enoate esters / Secondary alcohols / Cyclic alcohols and derivatives
show 7 more
Substituents: Cardanolide-glycoside / Steroidal glycoside / Oligosaccharide / 14-hydroxysteroid / Hydroxysteroid / Glycosyl compound / O-glycosyl compound / 2-furanone / Oxane / Cyclic alcohol
show 19 more
Molecular Framework: Aliphatic heteropolycyclic compounds
External Descriptors: cardenolide glycoside (CHEBI:28544) / cardanolide, Cardanolides and derivatives, Cardanolide and derivatives, Cardiac glycosides (C06955) / Cardanolides and derivatives (LMST01120018)

Targets

Details1. Sodium/potassium-transporting ATPase subunit alpha-1

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Inhibitor

General Function: Steroid hormone binding
Specific Function: 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 th...
Gene Name: ATP1A1
Uniprot ID: P05023
Uniprot Name: Sodium/potassium-transporting ATPase subunit alpha-1
Molecular Weight: 112895.01 Da

References

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:11309248]
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:123547]
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:131389]
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:132355]
Fricke U: [New aspects on the mode of action of cardiac glycosides]. Fortschr Med. 1976 Nov 11;94(32):1037-45. [PubMed:136410]
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. doi: 10.1016/j.ejphar.2009.08.039. Epub 2009 Sep 12. [PubMed:19751721]

Enzymes

Details1. Cytochrome P450 3A4

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Vitamin d3 25-hydroxylase activity
Specific Function: 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 react...
Gene Name: CYP3A4
Uniprot ID: P08684
Uniprot Name: Cytochrome P450 3A4
Molecular Weight: 57342.67 Da

References

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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Details2. Cholesterol side-chain cleavage enzyme, mitochondrial

Kind: Protein
Organism: Humans
Pharmacological action: Unknown

General Function: Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, nad(p)h as one donor, and incorporation of one atom of oxygen
Specific Function: Catalyzes the side-chain cleavage reaction of cholesterol to pregnenolone.
Gene Name: CYP11A1
Uniprot ID: P05108
Uniprot Name: Cholesterol side-chain cleavage enzyme, mitochondrial
Molecular Weight: 60101.87 Da

References

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:10381263]

Carriers

Details1. Serum albumin

Kind: Protein
Organism: Humans
Pharmacological action: No

General Function: Toxic substance binding
Specific Function: 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 colloid...
Gene Name: ALB
Uniprot ID: P02768
Uniprot Name: Serum albumin
Molecular Weight: 69365.94 Da

References

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:10202961]
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:10604823]
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:10774625]
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:11678517]

Transporters

Details1. Solute carrier organic anion transporter family member 1A2

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibit...
Gene Name: SLCO1A2
Uniprot ID: P46721
Uniprot Name: Solute carrier organic anion transporter family member 1A2
Molecular Weight: 74144.105 Da

References

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:8786566]

Details2. Solute carrier organic anion transporter family member 4C1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Inhibitor

General Function: Sodium-independent organic anion transmembrane transporter activity
Specific Function: 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 ...
Gene Name: SLCO4C1
Uniprot ID: Q6ZQN7
Uniprot Name: Solute carrier organic anion transporter family member 4C1
Molecular Weight: 78947.525 Da

References

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:14993604]

Details3. Multidrug resistance protein 1

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate

General Function: Xenobiotic-transporting atpase activity
Specific Function: Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: Multidrug resistance protein 1
Molecular Weight: 141477.255 Da

References

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:11284449]

Drug created on July 08, 2007 11:03 / Updated on December 14, 2018 05:36

Digitoxin

Identification

Structure for Digitoxin (DB01396)

Pharmacology

Interactions

References

Clinical Trials

Pharmacoeconomics

Properties

Spectra

Taxonomy

Targets

References

Enzymes

References

References

Carriers

References

Transporters

References

References

References