Digoxin

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Identification

Summary

Digoxin is a cardiac glycoside used in the treatment of mild to moderate heart failure and for ventricular response rate control in chronic atrial fibrillation.

Brand Names

Digox, Lanoxin

Generic Name

Digoxin

DrugBank Accession Number

DB00390

Background

Digoxin is one of the oldest cardiovascular medications used today.⁵ It is a common agent used to manage atrial fibrillation and the symptoms of heart failure.⁷ Digoxin is classified as a cardiac glycoside and was initially approved by the FDA in 1954.²⁵

This drug originates from the foxglove plant, also known as the Digitalis plant²¹, studied by William Withering, an English physician and botanist in the 1780s.^8,9 Prior to this, a Welsh family, historically referred to as the Physicians of Myddvai, formulated drugs from this plant. They were one of the first to prescribe cardiac glycosides, according to ancient literature dating as early as the 1250s.⁹

Type

Small Molecule

Groups

Approved

Structure

Similar Structures

Weight: Average: 780.9385
Monoisotopic: 780.429606756
Chemical Formula: C₄₁H₆₄O₁₄

Synonyms

12β-hydroxydigitoxin
Digossina
Digoxin
Digoxina
Digoxine
Digoxinum

External IDs

NSC-95100

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Pharmacology

Indication

Digoxin is indicated in the following conditions: 1) For the treatment of mild to moderate heart failure in adult patients.²⁵ 2) To increase myocardial contraction in children diagnosed with heart failure.²⁵ 3) To maintain control ventricular rate in adult patients diagnosed with chronic atrial fibrillation.²⁵

In adults with heart failure, when it is clinically possible, digoxin should be administered in conjunction with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor for optimum effects.²⁵

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Associated Conditions

Indication Type	Indication	Approval Level	Age Group	Patient Characteristics	Dose Form
Maintenance of	Myocardial contractility	••••••••••••	•••••••••	••••• •••••••	•••••••••• ••••••
Treatment of	Mild, moderate heart failure	••••••••••••	•••••		•••••••••• ••••••
Management of	Ventricular dysrhythmias	••••••••••••	•••••		•••••••••• ••••••

Contraindications & Blackbox Warnings

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Pharmacodynamics

Digoxin is a positive inotropic and negative chronotropic drug⁷, meaning that it increases the force of the heartbeat and decreases the heart rate.²³ The decrease in heart rate is particularly useful in cases of atrial fibrillation, a condition characterized by a fast and irregular heartbeat.¹³ The relief of heart failure symptoms during digoxin therapy has been demonstrated in clinical studies by increased exercise capacity and reduced hospitalization due to heart failure and reduced heart failure-related emergency medical visits.²⁵ Digoxin has a narrow therapeutic window.²⁵

A note on cardiovascular risk

Digoxin poses a risk of rapid ventricular response that can cause ventricular fibrillation in patients with an accessory atrioventricular (AV) pathway. Cardiac arrest as a result of ventricular fibrillation is fatal.²⁵ An increased risk of fatal severe or complete heart block is present in individuals with pre-existing sinus node disease and AV block who take digoxin.²⁵

Mechanism of action

Digoxin exerts hemodynamic, electrophysiologic, and neurohormonal effects on the cardiovascular system.⁷ It reversibly inhibits the Na-K ATPase enzyme, leading to various beneficial effects. The Na-K ATPase enzyme functions to maintain the intracellular environment by regulating the entry and exit of sodium, potassium, and calcium (indirectly). Na-K ATPase is also known as the sodium pump²⁵. The inhibition of the sodium pump by digoxin increases intracellular sodium and increases the calcium level in the myocardial cells, causing an increased contractile force of the heart.^25,11 This improves the left ventricular ejection fraction (EF), an important measure of cardiac function.^7,22

Digoxin also stimulates the parasympathetic nervous system via the vagus nerve²⁰ leading to sinoatrial (SA) and atrioventricular (AV) node effects, decreasing the heart rate.^25,7 Part of the pathophysiology of heart failure includes neurohormonal activation, leading to an increase in norepinephrine. Digoxin helps to decrease norepinephrine levels through activation of the parasympathetic nervous system.⁷

Target	Actions	Organism
ASodium/potassium-transporting ATPase subunit alpha-2	inhibitor	Humans
ASodium/potassium-transporting ATPase subunit alpha-3	inhibitor	Humans
ASodium/potassium-transporting ATPase subunit beta-1	inhibitor	Humans
ASodium/potassium-transporting ATPase subunit beta-2	inhibitor	Humans
ASodium/potassium-transporting ATPase subunit beta-3	inhibitor	Humans
ASolute carrier organic anion transporter family member 4C1	modulator	Humans
ASodium/potassium-transporting ATPase subunit alpha-1	inhibitor	Humans

Absorption

Digoxin is approximately 70-80% absorbed in the first part of the small bowel.⁶ The bioavailability of an oral dose varies from 50-90%, however, oral gelatinized capsules of digoxin are reported to have a bioavailability of 100%.¹⁰ Tmax, or the time to reach the maximum concentration of digoxin was measured to be 1.0 h in one clinical study of healthy patients taking 0.25 mg of digoxin with a placebo.¹⁹ Cmax, or maximum concentration, was 1.32 ± 0.18 ng/ml−1 in the same study, and AUC (area under the curve) was 12.5 ± 2.38 ng/ml−1.¹⁹ If digoxin is ingested after a meal, absorption is slowed but this does not change the total amount of absorbed drug. If digoxin is taken with meals that are in fiber, absorption may be decreased.²⁴

A note on gut bacteria

An oral dose of digoxin may be transformed into pharmacologically inactive products by bacteria in the colon. Studies have indicated that 10% of patients receiving digoxin tablets will experience the degradation of at least 40% of an ingested dose of digoxin by gut bacteria. Several antibiotics may increase the absorption of digoxin in these patients, due to the elimination of gut bacteria, which normally cause digoxin degradation.²⁵

A note on malabsorption

Patients with malabsorption due to a variety of causes may have a decreased ability to absorb digoxin.²⁵ P-glycoprotein, located on cells in the intestine, may interfere with digoxin pharmacokinetics, as it is a substrate of this efflux transporter. P-glycoprotein can be induced by other drugs, therefore reducing the effects of digoxin by increasing its efflux in the intestine.²⁵

Volume of distribution

This drug is widely distributed in the body, and is known to cross the blood-brain barrier and the placenta.^25,6 The apparent volume of distribution of digoxin is 475-500 L.²⁵ A large portion of digoxin is distributed in the skeletal muscle followed by the heart and kidneys.⁶ It is important to note that the elderly population, generally having a decreased muscle mass, may show a lower volume of digoxin distribution.²⁵

Protein binding

Digoxin protein binding is approximately 25%.²⁵ It is mainly bound to albumin.⁶

Metabolism

About 13% of a digoxin dose is found to be metabolized in healthy subjects. Several urinary metabolites of digoxin exist, including dihydrodigoxin and digoxigenin bisdigitoxoside. Their glucuronidated and sulfated conjugates are thought to be produced through the process of hydrolysis, oxidation, and additionally, conjugation. The cytochrome P-450 system does not play a major role in digoxin metabolism, nor does this drug induce or inhibit the enzymes in this system.²⁵

Hover over products below to view reaction partners

Digoxin
- Dihydrodigoxin
- Digoxigenin bisdigitoxoside

Route of elimination

The elimination of digoxin is proportional to the total dose, following first order kinetics. After intravenous (IV) administration to healthy subjects, 50-70% of the dose is measured excreted as unchanged digoxin in the urine. Approximately 25 to 28% of digoxin is eliminated outside of the kidney. Biliary excretion appears to be of much less importance than renal excretion.⁶

Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues.²⁵

Half-life

Digoxin has a half-life of 1.5-2 days in healthy subjects.²⁵ The half-life in patients who do not pass urine, usually due to renal failure, is prolonged to 3.5-5 days. Since most of the drug is distributed extravascularly, dialysis and exchange transfusion are not optimal methods for the removal of digoxin.²⁵

Clearance

The clearance of digoxin closely correlates to creatinine clearance, and does not depend on urinary flow. Individuals with renal impairment or failure may exhibit extensively prolonged half-lives. It is therefore important to titrate the dose accordingly and regularly monitor serum digoxin levels.²⁵ One pharmacokinetic study measured the mean body clearance of intravenous digoxin to be 88 ± 44ml/min/l.73 m².¹⁶ Another study provided mean clearance values of 53 ml/min/1.73 m² in men aged 73-81 and 83 ml/min/1.73 m² in men aged 20-33 years old after an intravenous digoxin dose.¹⁵

Adverse Effects

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Toxicity

Oral TDLO (human female): 100 ug/kg, Oral TDLO (human male): 75 ug/kg, Oral LD50 (rat): 28270 ug/kg^MSDS

Digoxin toxicity can occur in cases of supratherapeutic dose ingestion or as a result of chronic overexposure.²⁰ Digoxin toxicity may be manifested by symptoms of nausea, vomiting, visual changes, in addition to arrhythmia. Older age, lower body weight, and decreased renal function or electrolyte abnormalities lead to an increased risk of digoxin toxicity.²⁵

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Digoxin which could result in a higher serum level.
Abaloparatide	The risk or severity of adverse effects can be increased when Abaloparatide is combined with Digoxin.
Abemaciclib	The serum concentration of Abemaciclib can be increased when it is combined with Digoxin.
Abrocitinib	The serum concentration of Digoxin can be increased when it is combined with Abrocitinib.
Acarbose	The serum concentration of Digoxin can be decreased when it is combined with Acarbose.

Food Interactions

Avoid multivalent ions. Calcium and aluminum containing products (including kaolin-pectin) may interfere with absorption) and digoxin administration must be separated by several hours.
Avoid potassium-containing products. They may cause arrhythmias when given with digoxin.
Avoid St. John's Wort. This drug can decrease digoxin levels.
Do not take with bran and high fiber foods. Separate administration of bran and high fiber foods from medication by at least 2 hours.

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Product Images

International/Other Brands

Agoxin (Aristopharma) / Cardiacin (Center) / Cardiogoxin (Medipharma) / Cardioxin (Oboi) / Cardoxin / Celoxin (Celon) / Centoxin (Opsonin) / Digacin (mibe) / Digazolan / Digocard-G (Klonal) / Digoxina (GlaxoSmithKline) / Eudigox (Teofarma) / Lanacordin (Kern) / Lanacrist / Lanadicor / Lanicor (Roche) / Lenoxin (GlaxoSmithKline)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Digoxin	Solution	0.05 mg/1mL	Oral	Precision Dose, Inc.	2017-01-19	2019-04-30
Digoxin	Solution	0.05 mg/1mL	Oral	Atlantic Biologicals Corps.	2004-08-26	Not applicable
Digoxin	Solution	0.05 mg/1mL	Oral	Precision Dose, Inc.	2012-05-04	2019-05-31
Digoxin	Solution	0.05 mg/1mL	Oral	Hikma Pharmaceuticals USA Inc.	2004-08-26	Not applicable
Digoxin Injection C.S.D.	Liquid	0.5 mg / 2 mL	Intramuscular; Intravenous	Sandoz S.P.A.	1994-12-31	Not applicable

Generic Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Apo-digoxin	Tablet	0.0625 mg	Oral	Apotex Corporation	2006-06-22	Not applicable
Apo-digoxin	Tablet	0.125 mg	Oral	Apotex Corporation	2006-06-22	Not applicable
Apo-digoxin	Tablet	0.25 mg	Oral	Apotex Corporation	2006-06-22	Not applicable
Digitek	Tablet	0.25 mg/1	Oral	Mylan Institutional Inc.	2015-05-06	2023-02-28
Digitek	Tablet	0.125 mg/1	Oral	Mylan Institutional Inc.	2015-05-06	2022-12-31

Over the Counter Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
ไดซิน	Solution	0.25 mg/1ml	Oral	ห้างหุ้นส่วนจำกัด ภิญโญฟาร์มาซี	2008-12-29	Not applicable

Chemical Identifiers

UNII: 73K4184T59
CAS number: 20830-75-5
InChI Key: LTMHDMANZUZIPE-PUGKRICDSA-N
InChI: InChI=1S/C41H64O14/c1-19-36(47)28(42)15-34(50-19)54-38-21(3)52-35(17-30(38)44)55-37-20(2)51-33(16-29(37)43)53-24-8-10-39(4)23(13-24)6-7-26-27(39)14-31(45)40(5)25(9-11-41(26,40)48)22-12-32(46)49-18-22/h12,19-21,23-31,33-38,42-45,47-48H,6-11,13-18H2,1-5H3/t19-,20-,21-,23-,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,11R,11aS)-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,11-dihydroxy-9a,11a-dimethyl-hexadecahydro-1H-cyclopenta[a]phenanthren-1-yl]-2,5-dihydrofuran-2-one
SMILES: [H][C@]12CC[C@]3([H])[C@]([H])(C[C@@H](O)[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

References

Synthesis Reference

Wolfgang Voigtlander, Fritz Kaiser, Wolfgang Schaumann, Kurt Stach, "Preparation of C22-alkyl derivative of digoxin." U.S. Patent US3981862, issued October, 1972.

US3981862

General References

Thompson DF, Carter JR: Drug-induced gynecomastia. Pharmacotherapy. 1993 Jan-Feb;13(1):37-45. [Article]
Doering W, Konig E, Sturm W: [Digitalis intoxication: specifity and significance of cardiac and extracardiac symptoms. part I: Patients with digitalis-induced arrhythmias (author's transl)]. Z Kardiol. 1977 Mar;66(3):121-8. [Article]
Kaplanski J, Weinhouse E, Topaz M, Genchik G: Verapamil and digoxin: interactions in the rat. Res Commun Chem Pathol Pharmacol. 1983 Dec;42(3):377-88. [Article]
Flanagan RJ, Jones AL: Fab antibody fragments: some applications in clinical toxicology. Drug Saf. 2004;27(14):1115-33. [Article]
MacLeod-Glover N, Mink M, Yarema M, Chuang R: Digoxin toxicity: Case for retiring its use in elderly patients? Can Fam Physician. 2016 Mar;62(3):223-8. [Article]
Iisalo E: Clinical pharmacokinetics of digoxin. Clin Pharmacokinet. 1977 Jan-Feb;2(1):1-16. doi: 10.2165/00003088-197702010-00001. [Article]
Ziff OJ, Kotecha D: Digoxin: The good and the bad. Trends Cardiovasc Med. 2016 Oct;26(7):585-95. doi: 10.1016/j.tcm.2016.03.011. Epub 2016 Mar 31. [Article]
Whayne TF Jr: Clinical Use of Digitalis: A State of the Art Review. Am J Cardiovasc Drugs. 2018 Dec;18(6):427-440. doi: 10.1007/s40256-018-0292-1. [Article]
Norn S, Kruse PR: [Cardiac glycosides: From ancient history through Withering's foxglove to endogeneous cardiac glycosides]. Dan Medicinhist Arbog. 2004:119-32. [Article]
Currie GM, Wheat JM, Kiat H: Pharmacokinetic considerations for digoxin in older people. Open Cardiovasc Med J. 2011;5:130-5. doi: 10.2174/1874192401105010130. Epub 2011 Jun 15. [Article]
Mangoni ME, Nargeot J: Genesis and regulation of the heart automaticity. Physiol Rev. 2008 Jul;88(3):919-82. doi: 10.1152/physrev.00018.2007. [Article]
Vincent JL: Understanding cardiac output. Crit Care. 2008;12(4):174. doi: 10.1186/cc6975. Epub 2008 Aug 22. [Article]
Gutierrez C, Blanchard DG: Diagnosis and Treatment of Atrial Fibrillation. Am Fam Physician. 2016 Sep 15;94(6):442-52. [Article]
Virgadamo S, Charnigo R, Darrat Y, Morales G, Elayi CS: Digoxin: A systematic review in atrial fibrillation, congestive heart failure and post myocardial infarction. World J Cardiol. 2015 Nov 26;7(11):808-16. doi: 10.4330/wjc.v7.i11.808. [Article]
Ewy GA, Kapadia GG, Yao L, Lullin M, Marcus FI: Digoxin metabolism in the elderly. Circulation. 1969 Apr;39(4):449-53. [Article]
Koup JR, Jusko WJ, Elwood CM, Kohli RK: Digoxin pharmacokinetics: role of renal failure in dosage regimen design. Clin Pharmacol Ther. 1975 Jul;18(1):9-21. doi: 10.1002/cpt19751819. [Article]
Schmidt TA, Bundgaard H, Olesen HL, Secher NH, Kjeldsen K: Digoxin affects potassium homeostasis during exercise in patients with heart failure. Cardiovasc Res. 1995 Apr;29(4):506-11. [Article]
Watanabe Y, Okumura K, Hashimoto H, Ito T, Ogawa K, Satake T: Effects of digoxin on acetylcholine and norepinephrine concentrations in rat myocardium. J Cardiovasc Pharmacol. 1989 May;13(5):702-8. [Article]
Schwartz JI, Agrawal NG, Wehling M, Musser BJ, Gumbs CP, Michiels N, De Smet M, Wagner JA: Evaluation of the pharmacokinetics of digoxin in healthy subjects receiving etoricoxib. Br J Clin Pharmacol. 2008 Dec;66(6):811-7. doi: 10.1111/j.1365-2125.2008.03285.x. Epub 2008 Sep 24. [Article]
Rameez Rehman; Ofek Hai. (2018). Digitalis Toxicity. StatPearls Publishing.
IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Lyon (FR) (2016). Some Drugs and Herbal Products. International Agency for Research on Cancer.
A Kosaraju (2019). Left Ventricular Ejection Fraction. StatPearls.
Digoxin pharmacokinetics [Link]
MedSafe NZ: Lanoxin [Link]
FDA Approved Drug Products: Lanoxin (digoxin) oral tablets [Link]

External Links

Human Metabolome Database: HMDB0001917
KEGG Drug: D00298
KEGG Compound: C06956
PubChem Compound: 2724385
PubChem Substance: 46508524
ChemSpider: 2006532
BindingDB: 46355
RxNav: 3407
ChEBI: 4551
ChEMBL: CHEMBL1751
ZINC: ZINC000242548690
Therapeutic Targets Database: DAP000744
PharmGKB: PA449319
PDBe Ligand: DGX
RxList: RxList Drug Page
Drugs.com: Drugs.com Drug Page
Wikipedia: Digoxin

PDB Entries

1igj / 3b0w / 4ret / 7ddh

MSDS

Download (29 KB)

Clinical Trials

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
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Not Available	Active Not Recruiting	Not Available	Transgendered Persons	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Atrial Fibrillation	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Atrial Fibrillation / Heart Failure	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Congenital Heart Disease (CHD)	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Medically induced abortion	2	somestatus	stop reason	just information to hide

Pharmacoeconomics

Manufacturers

Glaxosmithkline llc
Roxane laboratories inc
Abraxis pharmaceutical products
Baxter healthcare corp anesthesia and critical care
Hospira inc
Sandoz canada inc
Wyeth ayerst laboratories
Actavis totowa llc
Caraco pharmaceutical laboratories ltd
Impax laboratories inc
Jerome stevens pharmaceuticals inc
West ward pharmaceutical corp
Smithkline beecham corp dba glaxosmithkline

Packagers

Advanced Pharmaceutical Services Inc.
Amerisource Health Services Corp.
Apotheca Inc.
A-S Medication Solutions LLC
Baxter International Inc.
C.O. Truxton Inc.
Caraco Pharmaceutical Labs
Cardinal Health
Comprehensive Consultant Services Inc.
Dept Health Central Pharmacy
Direct Dispensing Inc.
Dispensing Solutions
Diversified Healthcare Services Inc.
Draxis Specialty Pharmaceuticals Inc.
DSM Corp.
Duramed
General Injectables and Vaccines Inc.
GlaxoSmithKline Inc.
Global Pharmaceuticals
Heartland Repack Services LLC
Hospira Inc.
Jerome Stevens Pharmaceuticals Inc.
Kaiser Foundation Hospital
Kraft Pharmaceutical Co. Inc.
Lake Erie Medical and Surgical Supply
Lannett Co. Inc.
Liberty Pharmaceuticals
Major Pharmaceuticals
Mckesson Corp.
Murfreesboro Pharmaceutical Nursing Supply
Neuman Distributors Inc.
Nucare Pharmaceuticals Inc.
Palmetto Pharmaceuticals Inc.
PCA LLC
PD-Rx Pharmaceuticals Inc.
Pharmedix
Physicians Total Care Inc.
Prepackage Specialists
Prepak Systems Inc.
Remedy Repack
Resource Optimization and Innovation LLC
Roxane Labs
Sandhills Packaging Inc.
Sandoz
Savage Labs
Southwood Pharmaceuticals
Spectrum Pharmaceuticals
Talbert Medical Management Corp.
UDL Laboratories
Va Cmop Dallas
Vangard Labs Inc.
West-Ward Pharmaceuticals

Dosage Forms

Form	Route	Strength
Injection, solution
Injection	Intramuscular; Intravenous	0.25 mg/1.0mL
Injection	Intramuscular; Intravenous	0.25 mg/1mL
Injection, solution	Intramuscular; Intravenous; Parenteral	250 ug/1mL
Solution	Oral	0.05 mg/1mL
Tablet	Oral
Tablet	Oral	0.125 mg/1
Tablet	Oral	0.125 mg/301
Tablet	Oral	0.25 mg/301
Tablet	Oral	0.250 mg/1
Tablet	Oral	125 ug/1
Tablet	Oral	250 ug/1
Liquid	Intramuscular; Intravenous	0.5 mg / 2 mL
Solution	Oral	0.75 mg
Capsule, liquid filled	Oral	0.25 mg
Capsule	Oral	0.1 MG
Capsule	Oral	0.125 MG
Capsule	Oral	0.2 MG
Capsule	Oral	0.250 MG
Injection	Intramuscular; Intravenous	0.25 MG/ML
Solution	Parenteral	500.00 mcg
Capsule, liquid filled	Oral	100 ug/1
Capsule, liquid filled	Oral	200 ug/1
Injection, solution	Intramuscular; Intravenous	100 ug/1mL
Injection, solution	Intramuscular; Intravenous	250 ug/1mL
Injection, solution	Parenteral	0.5 MG/2ML
Solution / drops	Oral	0.5 MG/ML
Syrup		0.05 MG/ML
Tablet	Oral	0.0625 mg/1
Tablet	Oral	0.1875 mg/1
Tablet	Oral	0.25 mg/1
Tablet	Oral	0.250 mg
Tablet	Oral	00625 MG
Tablet	Oral	0125 MG
Tablet	Oral	0250 MG
Elixir	Oral	0.05 mg/1ml
Tablet	Oral	250 mcg
Liquid	Oral	.05 mg / mL
Liquid	Intramuscular; Intravenous	.05 mg / mL
Liquid	Intramuscular; Intravenous	.25 mg / mL
Injection	Intramuscular; Intravenous	0.5 mg/2ml
Injection	Intravenous	0.5 MG/2ML
Injection	Parenteral	0.5 mg/2ml
Elixir	Oral	50 mcg/ml
Elixir	Oral	0.05 mg/ml
Tablet	Oral	62.5 MCG
Tablet	Oral	.0625 mg
Tablet	Oral	.125 mg
Solution	Parenteral	500.000 mcg
Tablet	Oral	.25 mg
Liquid	Intramuscular; Intravenous	0.05 mg / 1 mL
Solution	Oral	0.05 mg / mL
Tablet	Oral	0.125 mg
Elixir	Oral	0.05 mg/60mL
Elixir	Oral	5.000 mg
Tablet	Oral	0.0625 mg
Tablet	Oral	0.25 mg
Solution	Oral	0.25 mg/1ml

Prices

Unit description	Cost	Unit
Digibind 38 mg vial	727.91USD	vial
Digifab 40 mg vial	615.6USD	vial
Digoxin powder	450.28USD	g
Digoxin 0.05 mg/ml Solution 60ml Bottle	36.99USD	bottle
Lanoxin ped 0.1 mg/ml ampul	6.91USD	ml
Digoxin Pediatric 0.05 mg/ml	6.79USD	ml
Digoxin 0.25 mg/ml	2.91USD	ml
Lanoxin 0.25 mg/ml ampul	1.44USD	ml
Lanoxin 0.125 mg tablet	0.73USD	tablet
Lanoxin 0.25 mg tablet	0.66USD	tablet
Digoxin 0.125 mg tablet	0.64USD	tablet
Digoxin 0.25 mg tablet	0.62USD	tablet
Digoxin 0.25 mg/ml ampul	0.61USD	ml
Lanoxin Pediatric 0.05 mg/ml Elixir	0.41USD	ml
Lanoxicaps 0.1 mg capsule	0.4USD	capsule
Lanoxin 125 mcg tablet	0.3USD	tablet
Lanoxin 250 mcg tablet	0.3USD	tablet
Digitek 125 mcg tablet	0.28USD	tablet
Digitek 250 mcg tablet	0.28USD	tablet
Lanoxicaps 0.05 mg capsule	0.28USD	capsule
Toloxin 0.0625 mg Tablet	0.27USD	tablet
Toloxin 0.125 mg Tablet	0.27USD	tablet
Toloxin 0.25 mg Tablet	0.27USD	tablet
Digoxin 125 mcg tablet	0.22USD	tablet
Digoxin 250 mcg tablet	0.22USD	tablet

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)	230-265	https://monographs.iarc.fr/wp-content/uploads/2018/06/mono108-13.pdf
boiling point (°C)	931.6	https://www.lookchem.com/Digoxin/
water solubility	64.8 mg/L (at 25 °C)	https://monographs.iarc.fr/wp-content/uploads/2018/06/mono108-13.pdf
logP	2.37	http://www.t3db.ca/toxins/T3D2670
pKa	-3, 7.15	https://monographs.iarc.fr/wp-content/uploads/2018/06/mono108-13.pdf

Predicted Properties

Property	Value	Source
Water Solubility	0.127 mg/mL	ALOGPS
logP	1.04	ALOGPS
logP	2.37	Chemaxon
logS	-3.8	ALOGPS
pKa (Strongest Acidic)	7.15	Chemaxon
pKa (Strongest Basic)	-3	Chemaxon
Physiological Charge	-1	Chemaxon
Hydrogen Acceptor Count	13	Chemaxon
Hydrogen Donor Count	6	Chemaxon
Polar Surface Area	203.06 Å²	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	193.23 m³·mol^-1	Chemaxon
Polarizability	84.8 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	+	0.941
Blood Brain Barrier	-	0.7241
Caco-2 permeable	-	0.8957
P-glycoprotein substrate	Substrate	0.8586
P-glycoprotein inhibitor I	Non-inhibitor	0.5325
P-glycoprotein inhibitor II	Non-inhibitor	0.6209
Renal organic cation transporter	Non-inhibitor	0.8621
CYP450 2C9 substrate	Non-substrate	0.855
CYP450 2D6 substrate	Non-substrate	0.9116
CYP450 3A4 substrate	Substrate	0.7366
CYP450 1A2 substrate	Non-inhibitor	0.9261
CYP450 2C9 inhibitor	Non-inhibitor	0.9196
CYP450 2D6 inhibitor	Non-inhibitor	0.9359
CYP450 2C19 inhibitor	Non-inhibitor	0.9385
CYP450 3A4 inhibitor	Non-inhibitor	0.9279
CYP450 inhibitory promiscuity	Low CYP Inhibitory Promiscuity	0.9279
Ames test	Non AMES toxic	0.9233
Carcinogenicity	Non-carcinogens	0.9668
Biodegradation	Not ready biodegradable	0.9555
Rat acute toxicity	4.4721 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.9818
hERG inhibition (predictor II)	Inhibitor	0.8051

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

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-03e9-0001002900-1b84fdb6d42982322279
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0201015900-ea7a6eeecde03c10e8cb
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01q9-0931001800-00ca705a246f71e1c990
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-0600015900-5cfb26c58151cdfb9d6c
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-001i-2923053600-2c253f3c8a0cf30f7b61
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-003b-0420227900-cf3c7cc6a4b1484591d6

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å²)	Source type	Source
[M-H]-	278.080378	predicted	DarkChem Lite v0.1.0
[M-H]-	297.797378	predicted	DarkChem Lite v0.1.0
[M-H]-	283.021178	predicted	DarkChem Lite v0.1.0
[M-H]-	278.416878	predicted	DarkChem Lite v0.1.0
[M-H]-	262.47165	predicted	DeepCCS 1.0 (2019)
[M+H]+	277.506778	predicted	DarkChem Lite v0.1.0
[M+H]+	296.514178	predicted	DarkChem Lite v0.1.0
[M+H]+	277.189778	predicted	DarkChem Lite v0.1.0
[M+H]+	264.1436	predicted	DeepCCS 1.0 (2019)
[M+Na]+	278.434778	predicted	DarkChem Lite v0.1.0
[M+Na]+	298.756778	predicted	DarkChem Lite v0.1.0
[M+Na]+	278.524278	predicted	DarkChem Lite v0.1.0
[M+Na]+	270.28168	predicted	DeepCCS 1.0 (2019)

Targets

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Details1. Sodium/potassium-transporting ATPase subunit alpha-2

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

General 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 the electrochemical gradient of sodium and potassium, providing the energy for active transport of various nutrients
Specific Function: ATP binding
Gene Name: ATP1A2
Uniprot ID: P50993
Uniprot Name: Sodium/potassium-transporting ATPase subunit alpha-2
Molecular Weight: 112264.385 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Details2. Sodium/potassium-transporting ATPase subunit alpha-3

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

General 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 the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients
Specific Function: amyloid-beta binding
Gene Name: ATP1A3
Uniprot ID: P13637
Uniprot Name: Sodium/potassium-transporting ATPase subunit alpha-3
Molecular Weight: 111747.51 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Details3. Sodium/potassium-transporting ATPase subunit beta-1

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

General Function: This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane. The beta subunit regulates, through assembly of alpha/beta heterodimers, the number of sodium pumps transported to the plasma membrane (PubMed:19694409). Plays a role in innate immunity by enhancing virus-triggered induction of interferons (IFNs) and interferon stimulated genes (ISGs). Mechanistically, enhances the ubiquitination of TRAF3 and TRAF6 as well as the phosphorylation of TAK1 and TBK1 (PubMed:34011520)
Specific Function: ATPase activator activity
Gene Name: ATP1B1
Uniprot ID: P05026
Uniprot Name: Sodium/potassium-transporting ATPase subunit beta-1
Molecular Weight: 35061.07 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Details4. Sodium/potassium-transporting ATPase subunit beta-2

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

General Function: This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane. The exact function of the beta-2 subunit is not known
Specific Function: ATPase activator activity
Gene Name: ATP1B2
Uniprot ID: P14415
Uniprot Name: Sodium/potassium-transporting ATPase subunit beta-2
Molecular Weight: 33366.925 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Details5. Sodium/potassium-transporting ATPase subunit beta-3

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

General Function: This is the non-catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of Na(+) and K(+) ions across the plasma membrane. The exact function of the beta-3 subunit is not known
Specific Function: ATPase activator activity
Gene Name: ATP1B3
Uniprot ID: P54709
Uniprot Name: Sodium/potassium-transporting ATPase subunit beta-3
Molecular Weight: 31512.34 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Details6. Solute carrier organic anion transporter family member 4C1

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

General Function: Mediates the transport of organic anions such as steroids (estrone 3-sulfate, chenodeoxycholate, glycocholate) and thyroid hormones (3,3',5-triiodo-L-thyronine (T3), L-thyroxine (T4)), in the kidney (PubMed:14993604, PubMed:19129463, PubMed:20610891). Capable of transporting cAMP and pharmacological substances such as digoxin, ouabain and methotrexate (PubMed:14993604). Transport is independent of sodium, chloride ion, and ATP (PubMed:14993604). Transport activity is stimulated by an acidic extracellular environment due to increased substrate affinity to the transporter (PubMed:19129463). The driving force for this transport activity is currently not known (By similarity). The role of hydrogencarbonate (HCO3(-), bicarbonate) as the probable counteranion that exchanges for organic anions is still not well defined (PubMed:19129463). Functions as an uptake transporter at the apical membrane, suggesting a role in renal reabsorption (By similarity). Involved in the renal secretion of the uremic toxin ADMA (N(omega),N(omega)-dimethyl-L-arginine or asymmetrical dimethylarginine), which is associated to cardiovascular events and mortality, and the structurally related amino acids L-arginine and L-homoarginine (a cardioprotective biomarker) (PubMed:30865704). Can act bidirectionally, suggesting a dual protective role of this transport protein; exporting L-homoarginine after being synthesized in proximal tubule cells, and mediating uptake of ADMA from the blood into proximal tubule cells where it is degraded by the enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) (PubMed:30865704, PubMed:32642843). May be involved in sperm maturation by enabling directed movement of organic anions and compounds within or between cells (By similarity). This ion-transporting process is important to maintain the strict epididymal homeostasis necessary for sperm maturation (By similarity). 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 (By similarity)
Specific Function: organic anion transmembrane transporter activity
Gene Name: SLCO4C1
Uniprot ID: Q6ZQN7
Uniprot Name: Solute carrier organic anion transporter family member 4C1
Molecular Weight: 78947.525 Da

References

Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]

Details7. Sodium/potassium-transporting ATPase subunit alpha-1

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

General 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 the electrochemical gradient of sodium and potassium ions, providing the energy for active transport of various nutrients (PubMed:29499166, PubMed:30388404). Could also be part of an osmosensory signaling pathway that senses body-fluid sodium levels and controls salt intake behavior as well as voluntary water intake to regulate sodium homeostasis (By similarity)
Specific Function: ATP binding
Gene Name: ATP1A1
Uniprot ID: P05023
Uniprot Name: Sodium/potassium-transporting ATPase subunit alpha-1
Molecular Weight: 112895.01 Da

References

Ravikumar A, Arun P, Devi KV, Augustine J, Kurup PA: Isoprenoid pathway and free radical generation and damage in neuropsychiatric disorders. Indian J Exp Biol. 2000 May;38(5):438-46. [Article]
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. [Article]
Ke YS, Liu ZF, Yang H, Yang T, Huang JS, Rui SB, Cheng GH, Wang YX: Effect of anti-digoxin antiserum on endoxin and membrane ATPase activity in hypoxia-reoxygenation induced myocardial injury. Acta Pharmacol Sin. 2000 Apr;21(4):345-7. [Article]
Kumar AR, Kurup PA: A hypothalamic digoxin mediated model for conscious and subliminal perception. J Neural Transm (Vienna). 2001;108(7):855-68. [Article]
Aizman O, Uhlen P, Lal M, Brismar H, Aperia A: Ouabain, a steroid hormone that signals with slow calcium oscillations. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13420-4. Epub 2001 Oct 30. [Article]
Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Rameez Rehman; Ofek Hai. (2018). Digitalis Toxicity. StatPearls Publishing.

Enzymes

Details1. Cholesterol side-chain cleavage enzyme, mitochondrial

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

General Function: A cytochrome P450 monooxygenase that catalyzes the side-chain hydroxylation and cleavage of cholesterol to pregnenolone, the precursor of most steroid hormones (PubMed:21636783). Catalyzes three sequential oxidation reactions of cholesterol, namely the hydroxylation at C22 followed with the hydroxylation at C20 to yield 20R,22R-hydroxycholesterol that is further cleaved between C20 and C22 to yield the C21-steroid pregnenolone and 4-methylpentanal (PubMed:21636783). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate and reducing the second into a water molecule. Two electrons are provided by NADPH via a two-protein mitochondrial transfer system comprising flavoprotein FDXR (adrenodoxin/ferredoxin reductase) and nonheme iron-sulfur protein FDX1 or FDX2 (adrenodoxin/ferredoxin) (PubMed:21636783)
Specific Function: cholesterol monooxygenase (side-chain-cleaving) activity
Gene Name: CYP11A1
Uniprot ID: P05108
Uniprot Name: Cholesterol side-chain cleavage enzyme, mitochondrial
Molecular Weight: 60101.87 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. [Article]
Wang SW, Pu HF, Kan SF, Tseng CI, Lo MJ, Wang PS: Inhibitory effects of digoxin and digitoxin on corticosterone production in rat zona fasciculata-reticularis cells. Br J Pharmacol. 2004 Aug;142(7):1123-30. Epub 2004 Jul 12. [Article]
Lin H, Wang SW, Tsai SC, Chen JJ, Chiao YC, Lu CC, Huang WJ, Wang GJ, Chen CF, Wang PS: Inhibitory effect of digoxin on testosterone secretion through mechanisms involving decreases of cyclic AMP production and cytochrome P450scc activity in rat testicular interstitial cells. Br J Pharmacol. 1998 Dec;125(8):1635-40. [Article]

Transporters

Property	Measurement	pH	Temperature (°C)	References
IC 50 (nM)	>50000	N/A	N/A	A15818

Details1. ATP-dependent translocase ABCB1

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

General Function: Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
Specific Function: ABC-type xenobiotic transporter activity
Gene Name: ABCB1
Uniprot ID: P08183
Uniprot Name: ATP-dependent translocase ABCB1
Molecular Weight: 141477.255 Da

References

Takara K, Tsujimoto M, Ohnishi N, Yokoyama T: Digoxin up-regulates MDR1 in human colon carcinoma Caco-2 cells. Biochem Biophys Res Commun. 2002 Mar 22;292(1):190-4. [Article]
Takara K, Takagi K, Tsujimoto M, Ohnishi N, Yokoyama T: Digoxin up-regulates multidrug resistance transporter (MDR1) mRNA and simultaneously down-regulates steroid xenobiotic receptor mRNA. Biochem Biophys Res Commun. 2003 Jun 20;306(1):116-20. [Article]
Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [Article]
Takara K, Tanigawara Y, Komada F, Nishiguchi K, Sakaeda T, Okumura K: Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs. Biol Pharm Bull. 1999 Dec;22(12):1355-9. [Article]
Yamazaki M, Neway WE, Ohe T, Chen I, Rowe JF, Hochman JH, Chiba M, Lin JH: In vitro substrate identification studies for p-glycoprotein-mediated transport: species difference and predictability of in vivo results. J Pharmacol Exp Ther. 2001 Mar;296(3):723-35. [Article]
Adachi Y, Suzuki H, Sugiyama Y: Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8. [Article]
Neuhoff S, Ungell AL, Zamora I, Artursson P: pH-dependent bidirectional transport of weakly basic drugs across Caco-2 monolayers: implications for drug-drug interactions. Pharm Res. 2003 Aug;20(8):1141-8. [Article]
Troutman MD, Thakker DR: Novel experimental parameters to quantify the modulation of absorptive and secretory transport of compounds by P-glycoprotein in cell culture models of intestinal epithelium. Pharm Res. 2003 Aug;20(8):1210-24. [Article]
Dagenais C, Graff CL, Pollack GM: Variable modulation of opioid brain uptake by P-glycoprotein in mice. Biochem Pharmacol. 2004 Jan 15;67(2):269-76. [Article]
Taipalensuu J, Tavelin S, Lazorova L, Svensson AC, Artursson P: Exploring the quantitative relationship between the level of MDR1 transcript, protein and function using digoxin as a marker of MDR1-dependent drug efflux activity. Eur J Pharm Sci. 2004 Jan;21(1):69-75. [Article]
Tanigawara Y, Okamura N, Hirai M, Yasuhara M, Ueda K, Kioka N, Komano T, Hori R: Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J Pharmacol Exp Ther. 1992 Nov;263(2):840-5. [Article]
Fromm MF, Kim RB, Stein CM, Wilkinson GR, Roden DM: Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments]. Circulation. 1999 Feb 2;99(4):552-7. [Article]
Soldner A, Christians U, Susanto M, Wacher VJ, Silverman JA, Benet LZ: Grapefruit juice activates P-glycoprotein-mediated drug transport. Pharm Res. 1999 Apr;16(4):478-85. [Article]
Collett A, Tanianis-Hughes J, Hallifax D, Warhurst G: Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo. Pharm Res. 2004 May;21(5):819-26. [Article]
Yamaguchi H, Yano I, Saito H, Inui K: Effect of cisplatin-induced acute renal failure on bioavailability and intestinal secretion of quinolone antibacterial drugs in rats. Pharm Res. 2004 Feb;21(2):330-8. [Article]
Takara K, Sakaeda T, Kakumoto M, Tanigawara Y, Kobayashi H, Okumura K, Ohnishi N, Yokoyama T: Effects of alpha-adrenoceptor antagonist doxazosin on MDR1-mediated multidrug resistance and transcellular transport. Oncol Res. 2009;17(11-12):527-33. [Article]
Jutabha P, Wempe MF, Anzai N, Otomo J, Kadota T, Endou H: Xenopus laevis oocytes expressing human P-glycoprotein: probing trans- and cis-inhibitory effects on [3H]vinblastine and [3H]digoxin efflux. Pharmacol Res. 2010 Jan;61(1):76-84. doi: 10.1016/j.phrs.2009.07.002. Epub 2009 Jul 21. [Article]
Chan LM, Cooper AE, Dudley AL, Ford D, Hirst BH: P-glycoprotein potentiates CYP3A4-mediated drug disappearance during Caco-2 intestinal secretory detoxification. J Drug Target. 2004;12(7):405-13. doi: 10.1080/10611860412331285224 . [Article]
Haslam IS, Jones K, Coleman T, Simmons NL: Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84). Biochem Pharmacol. 2008 Oct 1;76(7):850-61. doi: 10.1016/j.bcp.2008.07.020. Epub 2008 Jul 23. [Article]
Riganti C, Campia I, Polimeni M, Pescarmona G, Ghigo D, Bosia A: Digoxin and ouabain induce P-glycoprotein by activating calmodulin kinase II and hypoxia-inducible factor-1alpha in human colon cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):385-92. doi: 10.1016/j.taap.2009.07.026. Epub 2009 Jul 30. [Article]
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers [Link]

Details2. Solute carrier organic anion transporter family member 4C1

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

General Function: Mediates the transport of organic anions such as steroids (estrone 3-sulfate, chenodeoxycholate, glycocholate) and thyroid hormones (3,3',5-triiodo-L-thyronine (T3), L-thyroxine (T4)), in the kidney (PubMed:14993604, PubMed:19129463, PubMed:20610891). Capable of transporting cAMP and pharmacological substances such as digoxin, ouabain and methotrexate (PubMed:14993604). Transport is independent of sodium, chloride ion, and ATP (PubMed:14993604). Transport activity is stimulated by an acidic extracellular environment due to increased substrate affinity to the transporter (PubMed:19129463). The driving force for this transport activity is currently not known (By similarity). The role of hydrogencarbonate (HCO3(-), bicarbonate) as the probable counteranion that exchanges for organic anions is still not well defined (PubMed:19129463). Functions as an uptake transporter at the apical membrane, suggesting a role in renal reabsorption (By similarity). Involved in the renal secretion of the uremic toxin ADMA (N(omega),N(omega)-dimethyl-L-arginine or asymmetrical dimethylarginine), which is associated to cardiovascular events and mortality, and the structurally related amino acids L-arginine and L-homoarginine (a cardioprotective biomarker) (PubMed:30865704). Can act bidirectionally, suggesting a dual protective role of this transport protein; exporting L-homoarginine after being synthesized in proximal tubule cells, and mediating uptake of ADMA from the blood into proximal tubule cells where it is degraded by the enzyme dimethylarginine dimethylaminohydrolase 1 (DDAH1) (PubMed:30865704, PubMed:32642843). May be involved in sperm maturation by enabling directed movement of organic anions and compounds within or between cells (By similarity). This ion-transporting process is important to maintain the strict epididymal homeostasis necessary for sperm maturation (By similarity). 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 (By similarity)
Specific Function: organic anion transmembrane transporter activity
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. [Article]
Yamaguchi H, Sugie M, Okada M, Mikkaichi T, Toyohara T, Abe T, Goto J, Hishinuma T, Shimada M, Mano N: Transport of estrone 3-sulfate mediated by organic anion transporter OATP4C1: estrone 3-sulfate binds to the different recognition site for digoxin in OATP4C1. Drug Metab Pharmacokinet. 2010;25(3):314-7. [Article]

Details3. Bile salt export pump

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Substrate
Curator comments: Data regarding this transporter in relation to digoxin are limited in the literature. The results of one in vitro study suggest that this drug is transported by the bile salt export pump.

General Function: Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeostasis and consequently to lipid homeostasis through regulation of biliary lipid secretion in a bile salts dependent manner (PubMed:15791618, PubMed:16332456, PubMed:18985798, PubMed:19228692, PubMed:20010382, PubMed:20398791, PubMed:22262466, PubMed:24711118, PubMed:29507376, PubMed:32203132). Transports taurine-conjugated bile salts more rapidly than glycine-conjugated bile salts (PubMed:16332456). Also transports non-bile acid compounds, such as pravastatin and fexofenadine in an ATP-dependent manner and may be involved in their biliary excretion (PubMed:15901796, PubMed:18245269)
Specific Function: ABC-type bile acid transporter activity
Gene Name: ABCB11
Uniprot ID: O95342
Uniprot Name: Bile salt export pump
Molecular Weight: 146405.83 Da

References

Hagenbuch N, Reichel C, Stieger B, Cattori V, Fattinger KE, Landmann L, Meier PJ, Kullak-Ublick GA: Effect of phenobarbital on the expression of bile salt and organic anion transporters of rat liver. J Hepatol. 2001 Jun;34(6):881-7. [Article]

Details4. Solute carrier organic anion transporter family member 1A2

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

General Function: Na(+)-independent transporter that mediates the cellular uptake of a broad range of organic anions such as the endogenous bile salts cholate and deoxycholate, either in their unconjugated or conjugated forms (taurocholate and glycocholate), at the plasmam membrane (PubMed:19129463, PubMed:7557095). Responsible for intestinal absorption of bile acids (By similarity). Transports dehydroepiandrosterone 3-sulfate (DHEAS), a major circulating steroid secreted by the adrenal cortex, as well as estrone 3-sulfate and 17beta-estradiol 17-O-(beta-D-glucuronate) (PubMed:11159893, PubMed:12568656, PubMed:19129463, PubMed:23918469, PubMed:25560245, PubMed:9539145). Mediates apical uptake of all-trans-retinol (atROL) across human retinal pigment epithelium, which is essential to maintaining the integrity of the visual cycle and thus vision (PubMed:25560245). Involved in the uptake of clinically used drugs (PubMed:17301733, PubMed:20686826, PubMed:27777271). Capable of thyroid hormone transport (both T3 or 3,3',5'-triiodo-L-thyronine, and T4 or L-tyroxine) (PubMed:19129463, PubMed:20358049). Also transports prostaglandin E2 (PubMed:19129463). Plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells (By similarity). May also play a role in the reuptake of neuropeptides such as substance P/TAC1 and vasoactive intestinal peptide/VIP released from retinal neurons (PubMed:25132355). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drugs methotrexate and paclitaxel (PubMed:23243220). Shows a pH-sensitive substrate specificity which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLCO1A2
Uniprot ID: P46721
Uniprot Name: Solute carrier organic anion transporter family member 1A2
Molecular Weight: 74144.105 Da

References

Hagenbuch B, Adler ID, Schmid TE: Molecular cloning and functional characterization of the mouse organic-anion-transporting polypeptide 1 (Oatp1) and mapping of the gene to chromosome X. Biochem J. 2000 Jan 1;345 Pt 1:115-20. [Article]
Noe B, Hagenbuch B, Stieger B, Meier PJ: Isolation of a multispecific organic anion and cardiac glycoside transporter from rat brain. Proc Natl Acad Sci U S A. 1997 Sep 16;94(19):10346-50. [Article]

Details5. Organic solute transporter subunit alpha

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

General Function: Essential component of the Ost-alpha/Ost-beta complex, a heterodimer that acts as the intestinal basolateral transporter responsible for bile acid export from enterocytes into portal blood (PubMed:16317684). Efficiently transports the major species of bile acids (taurocholate) (PubMed:16317684). Taurine conjugates are transported more efficiently across the basolateral membrane than glycine-conjugated bile acids (By similarity). Can also transport steroids such as estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, therefore playing a role in the enterohepatic circulation of sterols (PubMed:16317684). Able to transport eicosanoids such as prostaglandin E2 (By similarity)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLC51A
Uniprot ID: Q86UW1
Uniprot Name: Organic solute transporter subunit alpha
Molecular Weight: 37734.575 Da

References

Seward DJ, Koh AS, Boyer JL, Ballatori N: Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta. J Biol Chem. 2003 Jul 25;278(30):27473-82. Epub 2003 Apr 28. [Article]
Ballatori N, Li N, Fang F, Boyer JL, Christian WV, Hammond CL: OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids. Front Biosci (Landmark Ed). 2009 Jan 1;14:2829-44. [Article]
Malinen MM, Ali I, Bezencon J, Beaudoin JJ, Brouwer KLR: Organic solute transporter OSTalpha/beta is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury. Am J Physiol Gastrointest Liver Physiol. 2018 May 1;314(5):G597-G609. doi: 10.1152/ajpgi.00310.2017. Epub 2018 Feb 8. [Article]

Details6. Organic solute transporter subunit beta

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

General Function: Essential component of the Ost-alpha/Ost-beta complex, a heterodimer that acts as the intestinal basolateral transporter responsible for bile acid export from enterocytes into portal blood (PubMed:16317684). Modulates SLC51A glycosylation, membrane trafficking and stability activities (PubMed:16317684). The Ost-alpha/Ost-beta complex efficiently transports the major species of bile acids (taurocholate) (PubMed:16317684). Taurine conjugates are transported more efficiently across the basolateral membrane than glycine-conjugated bile acids (By similarity). Can also transport steroids such as estrone 3-sulfate and dehydroepiandrosterone 3-sulfate, therefore playing a role in the enterohepatic circulation of sterols (PubMed:16317684). Able to transport eicosanoids such as prostaglandin E2 (By similarity)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLC51B
Uniprot ID: Q86UW2
Uniprot Name: Organic solute transporter subunit beta
Molecular Weight: 14346.195 Da

References

Seward DJ, Koh AS, Boyer JL, Ballatori N: Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta. J Biol Chem. 2003 Jul 25;278(30):27473-82. Epub 2003 Apr 28. [Article]
Ballatori N, Li N, Fang F, Boyer JL, Christian WV, Hammond CL: OST alpha-OST beta: a key membrane transporter of bile acids and conjugated steroids. Front Biosci (Landmark Ed). 2009 Jan 1;14:2829-44. [Article]
Malinen MM, Ali I, Bezencon J, Beaudoin JJ, Brouwer KLR: Organic solute transporter OSTalpha/beta is overexpressed in nonalcoholic steatohepatitis and modulated by drugs associated with liver injury. Am J Physiol Gastrointest Liver Physiol. 2018 May 1;314(5):G597-G609. doi: 10.1152/ajpgi.00310.2017. Epub 2018 Feb 8. [Article]

Details7. Solute carrier organic anion transporter family member 1B1

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

General Function: Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
Specific Function: bile acid transmembrane transporter activity
Gene Name: SLCO1B1
Uniprot ID: Q9Y6L6
Uniprot Name: Solute carrier organic anion transporter family member 1B1
Molecular Weight: 76447.99 Da

References

van Montfoort JE, Schmid TE, Adler ID, Meier PJ, Hagenbuch B: Functional characterization of the mouse organic-anion-transporting polypeptide 2. Biochim Biophys Acta. 2002 Aug 19;1564(1):183-8. [Article]
Dagenais C, Ducharme J, Pollack GM: Uptake and efflux of the peptidic delta-opioid receptor agonist. Neurosci Lett. 2001 Apr 6;301(3):155-8. [Article]
Sugiyama D, Kusuhara H, Shitara Y, Abe T, Meier PJ, Sekine T, Endou H, Suzuki H, Sugiyama Y: Characterization of the efflux transport of 17beta-estradiol-D-17beta-glucuronide from the brain across the blood-brain barrier. J Pharmacol Exp Ther. 2001 Jul;298(1):316-22. [Article]
Hagenbuch N, Reichel C, Stieger B, Cattori V, Fattinger KE, Landmann L, Meier PJ, Kullak-Ublick GA: Effect of phenobarbital on the expression of bile salt and organic anion transporters of rat liver. J Hepatol. 2001 Jun;34(6):881-7. [Article]
Gao B, Wenzel A, Grimm C, Vavricka SR, Benke D, Meier PJ, Reme CE: Localization of organic anion transport protein 2 in the apical region of rat retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2002 Feb;43(2):510-4. [Article]
Shitara Y, Sugiyama D, Kusuhara H, Kato Y, Abe T, Meier PJ, Itoh T, Sugiyama Y: Comparative inhibitory effects of different compounds on rat oatpl (slc21a1)- and Oatp2 (Slc21a5)-mediated transport. Pharm Res. 2002 Feb;19(2):147-53. [Article]

Drug created at June 13, 2005 13:24 / Updated at October 11, 2024 18:19

Digoxin

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