Details of the Drug

General Information of Drug (ID: DMWVIGP)

• Drug Name: Digitoxin
• Synonyms: Acedoxin; Asthenthilo; Cardidigin; Cardigin; Cardiolanata; Carditalin; Carditoxin; Coramedan; Cristapurat; Crystodigin; Digicor; Digilanid; Digilong; Digimed; Digimerck; Digipural; Digisidin; Digitoksim; Digitoksin; Digitophyllin; Digitossina; Digitoxina; Digitoxine; Digitoxinum; Digitoxoside; Digitoxosidum; Digitrin; Ditaven; Glucodigin; Lanatoxin; Lanostabil; Monodigitoxoside; Myodigin; Natigal; Pandigal; Panlanat; Purodigin; Purpurid; Tardigal; Unidigin; Crystalline digitalin; Digitaline cristallisee; Digitaline nativelle; Digitalinum verum; Digitossina [DCIT]; Digitoxigenin tridigitoxoside; LT00244784; Crystodigin (TN); De-Tone; Digitalin, crystalline; Digitaline (TN); Digitoxigenin-tridigitoxosid; Digitoxigenin-tridigitoxosid [German]; Digitoxina [INN-Spanish]; Digitoxine [INN-French]; Digitoxinum [INN-Latin]; Mono-digitoxid; Mono-digitoxid [German]; Mono-glycocard; Purodigin, crystalline; Tri-digitoxoside; Tri-digitoxoside [German]; Digitoxin [INN:BAN:JAN]; Digitoxin (JP15/USP/INN); Inhibits Na+/K+ ATPase; 5.beta.-Card-20(22)-enolide, 3.beta.,14-dihydroxy-, 3-[tris-(digitoxoside)]

Indication

Disease Entry	ICD 11	Status	REF
Arrhythmia	BC9Z	Approved	[1]
Congestive cardiac insufficiency	BD1Z	Approved	[1]
Heart failure	BD10-BD13	Approved	[1]

• Therapeutic Class: Antiarrhythmic Agents
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 2:
  Molecular Weight (mw); 764.9
  Logarithm of the Partition Coefficient (xlogp); 2.3
  Rotatable Bond Count (rotbonds); 7
  Hydrogen Bond Donor Count (hbonddonor); 5
  Hydrogen Bond Acceptor Count (hbondacc); 13
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 3: high solubility and low permeability [2]
  Bioavailability: 95% of drug becomes completely available to its intended biological destination(s) [3]
  Clearance: The drug present in the plasma can be removed from the body at the rate of 0.043 mL/min/kg [4]
  Elimination: 30% of drug is excreted from urine in the unchanged form [2]
  Half-life: The concentration or amount of drug in body reduced by one-half in 180 hours [4]
  Metabolism: The drug is metabolized via the hepatic []
  MRTD: The Maximum Recommended Therapeutic Dose (MRTD) of drug that ensured maximising efficacy and moderate side effect is 0.0000261 micromolar/kg/day [5]
  Unbound Fraction: The unbound fraction of drug in plasma is 0.066% [4]
  Vd: Fluid volume that would be required to contain the amount of drug present in the body at the same concentration as in the plasma 0.44 L/kg [4]
  Water Solubility: The ability of drug to dissolve in water is measured as 0.01 mg/mL [2]
• Chemical Identifiers:
  Formula: C41H64O13
  IUPAC Name: 3-[(3S,5R,8R,9S,10S,13R,14S,17R)-3-[(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-14-hydroxy-10,13-dimethyl-1,2,3,4,5,6,7,8,9,11,12,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]-2H-furan-5-one
  Canonical SMILES: C[C@@H]1[C@H]([C@H](C[C@@H](O1)O[C@@H]2[C@H](O[C@H](C[C@@H]2O)O[C@@H]3[C@H](O[C@H](C[C@@H]3O)O[C@H]4CC[C@]5([C@@H](C4)CC[C@@H]6[C@@H]5CC[C@]7([C@@]6(CC[C@@H]7C8=CC(=O)OC8)O)C)C)C)C)O)O
  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
  InChIKey: WDJUZGPOPHTGOT-XUDUSOBPSA-N
• Cross-matching ID:
  PubChem CID: 441207
  ChEBI ID: CHEBI:28544
  CAS Number: 71-63-6
  DrugBank ID: DB01396
  TTD ID: D0M3QP
  VARIDT ID: DR00239
  INTEDE ID: DR0497
• Repurposed Drugs (RPD): Click to Jump to the Detailed RPD Information of This Drug

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Sodium/potassium-transporting ATPase (SPT ATPase)	TTQ38E9	AT1A1_HUMAN ; AT1A2_HUMAN ; AT1A3_HUMAN ; AT1B1_HUMAN ; AT1B2_HUMAN ; AT1B3_HUMAN	Inhibitor	[6]

Drug Transporter (DTP)

DTP Name	DTP ID	UniProt ID	MOA	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[7]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[8]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Substrate	[9]
Sulfotransferase 1A1 (SULT1A1)	DEYWLRK	ST1A1_HUMAN	Substrate	[10]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Regulation of Drug Effects	[11]
Baculoviral IAP repeat-containing protein 5 (BIRC5)	OTILXZYL	BIRC5_HUMAN	Gene/Protein Processing	[12]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Gene/Protein Processing	[12]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Protein Interaction/Cellular Processes	[12]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Protein Interaction/Cellular Processes	[12]
Cellular tumor antigen p53 (TP53)	OTIE1VH3	P53_HUMAN	Gene/Protein Processing	[12]
Cyclin-dependent kinase 1 (CDK1)	OTW1SC2N	CDK1_HUMAN	Gene/Protein Processing	[12]
Cyclin-dependent kinase inhibitor 1 (CDKN1A)	OTQWHCZE	CDN1A_HUMAN	Gene/Protein Processing	[12]
Cyclin-dependent kinase inhibitor 1B (CDKN1B)	OTNY5LLZ	CDN1B_HUMAN	Gene/Protein Processing	[12]
Cytochrome c (CYCS)	OTBFALJD	CYC_HUMAN	Gene/Protein Processing	[12]

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Digitoxin (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Pasireotide	DMHM7JS	Moderate	Increased risk of bradycardia by the combination of Digitoxin and Pasireotide.	Cushing syndrome [5A70]	[13]
SODIUM CITRATE	DMHPD2Y	Minor	Decreased absorption of Digitoxin due to formation of complexes caused by SODIUM CITRATE.	Discovery agent [N.A.]	[14]
Stiripentol	DMMSDOY	Moderate	Decreased metabolism of Digitoxin caused by Stiripentol mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[15]
Lasmiditan	DMXLVDT	Moderate	Decreased clearance of Digitoxin due to the transporter inhibition by Lasmiditan.	Migraine [8A80]	[16]
Lanthanum carbonate	DMMJQSH	Moderate	Decreased absorption of Digitoxin due to formation of complexes caused by Lanthanum carbonate.	Mineral absorption/transport disorder [5C64]	[13]
Siponimod	DM2R86O	Major	Increased risk of atrioventricular block by the combination of Digitoxin and Siponimod.	Multiple sclerosis [8A40]	[17]
Fingolimod	DM5JVAN	Major	Increased risk of atrioventricular block by the combination of Digitoxin and Fingolimod.	Multiple sclerosis [8A40]	[18]
Ozanimod	DMT6AM2	Moderate	Increased risk of atrioventricular block by the combination of Digitoxin and Ozanimod.	Multiple sclerosis [8A40]	[19]
Temsirolimus	DMS104F	Moderate	Increased plasma concentrations of Digitoxin and Temsirolimus due to competitive inhibition of the same metabolic pathway.	Renal cell carcinoma [2C90]	[20]
Amisulpride	DMSJVAM	Moderate	Increased risk of ventricular arrhythmias by the combination of Digitoxin and Amisulpride.	Schizophrenia [6A20]	[21]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6782).
• [2] BDDCS applied to over 900 drugs
• [3] Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
• [4] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [5] Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose
• [6] Treatment of congestive heart failure--current status of use of digitoxin. Eur J Clin Invest. 2001;31 Suppl 2:10-7.
• [7] The association of ABCB1 polymorphisms and elevated serum digitoxin concentrations in geriatric patients. Eur J Clin Pharmacol. 2008 Apr;64(4):367-72.
• [8] Species differences in the toxicity and cytochrome P450 IIIA-dependent metabolism of digitoxin. Mol Pharmacol. 1991 Nov;40(5):859-67.
• [9] Use of a human liver microsome bank in drug glucuronidation studies. Toxicol In Vitro. 1991;5(5-6):559-62.
• [10] Hydroxysteroid sulfotransferase and a specific UDP-glucuronosyltransferase are involved in the metabolism of digitoxin in man. Naunyn Schmiedebergs Arch Pharmacol. 1992 Aug;346(2):226-33.
• [11] Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays. Toxicol In Vitro. 2016 Apr;32:138-45. doi: 10.1016/j.tiv.2015.12.009. Epub 2015 Dec 17.
• [12] Digitoxin and a synthetic monosaccharide analog inhibit cell viability in lung cancer cells. Toxicol Appl Pharmacol. 2012 Jan 1;258(1):51-60. doi: 10.1016/j.taap.2011.10.007. Epub 2011 Oct 18.
• [13] Canadian Pharmacists Association.
• [14] Allen MD, Greenblatt DJ, Harmatz JS, Smith TW "Effect of magnesium--aluminum hydroxide and kaolin--pectin on absorption of digoxin from tablets and capsules." J Clin Pharmacol 21 (1981): 26-30. [PMID: 7012189]
• [15] EMEA. European Medicines Agency "EPARs. European Union Public Assessment Reports.".
• [16] Product Information. Reyvow (lasmiditan). Lilly, Eli and Company, Indianapolis, IN.
• [17] Cerner Multum, Inc. "Australian Product Information.".
• [18] Product Information. Gilenya (fingolimod). Novartis Pharmaceuticals, East Hanover, NJ.
• [19] Product Information. Zeposia (ozanimod). Celgene Corporation, Summit, NJ.
• [20] Product Information. Prograf (tacrolimus). Fujisawa, Deerfield, IL.
• [21] Cerner Multum, Inc. "UK Summary of Product Characteristics.".