Drug Information

Drug (ID: DG00030) and It's Reported Resistant Information

• Name: Digoxin
• Synonyms: Digoxin; 20830-75-5; 12beta-Hydroxydigitoxin; Digoxine; Lanoxin; Lanoxicaps; Digossina; Digoxina; Digoxinum; Digosin; Lanicor; Digacin; Dilanacin; CHEBI:4551; MLS000069819; Lanacordin; Cardiogoxin; Eudigox; Davoxin; SMR000059217; Rougoxin; Mapluxin; Lenoxin; Lanacrist; Dynamos; Vanoxin; Neo-Lanicor; Lanoxin PG; Digoxin Pediatric; Digoxin Nativelle; SK-Digoxin; UNII-73K4184T59; Homolle's digitalin; Hemigoxine Nativelle; MFCD00003674; Digitek (TN); Lanoxicaps (TN); Lanoxin (TN); Digoxin (JP15/USP); (3beta,5beta,12beta)-3-{[2,6-dideoxy-beta-D-ribo-hexopyranosyl-(1->4)-2,6-dideoxy-beta-D-ribo-hexopyranosyl-(1->4)-2,6-dideoxy-beta-D-ribo-hexopyranosyl]oxy}-12,14-dihydroxycard-20(22)-enolide; 4-[(1S,2S,5S,7R,10R,11S,14R,15S,16R)-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}-11,16-dihydroxy-2,15-dimethyltetracyclo[8700^{2,7}; [3H]digoxin
• Indication:
  In total 2 Indication(s)
  Cardiac arrhythmia [ICD-11: BC9Z]; Approved; [1]
  Heart failure [ICD-11: BD10]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Heart failure [ICD-11: BD10]; [2]
• Target: Organic anion transporter M1 (SLCO4C1); SO4C1_HUMAN; [1]
• Target: Sodium/potassium-transporting ATPase (SPT ATPase); AT1A1_HUMAN AT1A2_HUMAN AT1A3_HUMAN AT1B1_HUMAN AT1B2_HUMAN AT1B3_HUMAN; [1]
• Formula: C41H64O14
• IsoSMILES: 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]5C[C@H]([C@]7([C@@]6(CC[C@@H]7C8=CC(=O)OC8)O)C)O)C)C)C)O)O
• 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
• InChIKey: LTMHDMANZUZIPE-PUGKRICDSA-N
• PubChem CID: 2724385
• ChEBI ID: CHEBI:4551
• TTD Drug ID: D02OZE
• VARIDT ID: DR00148
• INTEDE ID: DR0498
• DrugBank ID: DB00390

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-11: Circulatory system diseases

Heart failure [ICD-11: BD10]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [2]

• Molecule Alteration: Expression; Up-regulation
• Resistant Disease: Heart failure [ICD-11: BD10.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: LS-180 cells; Colon; Homo sapiens (Human); CVCL_0397
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Rhodamine 123 fluorometric assay
• Mechanism Description: Chronic use of Saint John's wort (SJW) has been shown to lower the bioavailability for a variety of co-administered drugs including indinavir, cyclosporin, and digoxin. Decreases in intestinal absorption through induction of the multidrug resistance transporter, P-glycoprotein (P-gp), may explain decreased bioavaila.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [1]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Heart failure [ICD-11: BD10.0]
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• Experiment for Molecule Alteration: Bi-directional transport assay
• Mechanism Description: In addition to expression in tumor cells, the ATP-dependent P-gp efflux transporter is localized in a variety of normal tissues including the apical membranes of the epithelial cells lining the luminal surface of the enterocytes in the small intestine/gastrointestinal tract, the biliary canalicular membranes of hepatocytes, the apical luminal membranes of the proximal tubular epithelial cells in the kidney, and the plasma membranes of brain capillary endothelial cells forming the blood-brain barrier (BBB). P-gp in these tissues functions as a drug efflux pump greatly affecting substrate absorption, distribution, and excretion. Loxapine (as the succinate salt) was evaluated as a P-gp substrate, and inhibitor of P-gp mediated transport of digoxin in vitro in Caco-2 cells. Loxapine was not a substrate for P-gp but did exhibit weak-to-moderate inhibition (IC50 = 9.1 uM).

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [3], [4], [5]

• Molecule Alteration: Expression; Down-regulation
• Sensitive Disease: Heart failure [ICD-11: BD10.0]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: MDCk-MDR1(Canis lupus familiaris (Dog)); Kidney; Homo sapiens (Human); CVCL_S586
• In Vitro Model: IPS cells; Colon; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Ussing chamber system assay
• Mechanism Description: Digoxin and fexofenadine (each 5 uM) were selected as P-gp substrates, and sulfasalazine and rosuvastatin (each 5 uM) were selected as BCRP substrates to evaluate the efflux transport mediated by P-gp and BCRP. PSC833 (15 uM) and ko143 (15 uM) were used as typical inhibitors of P-gp and BCRP, respectively. Serosal-to-mucosal transport of all the tested P-gp and BCRP substrate drugs was significantly decreased or tended to decrease in the presence of P-gp/BCRP inhibitor cocktail.

References

• Ref 1: Loxapine P-glycoprotein interactions in vitro. Drug Metab Lett. 2012 Mar;6(1):26-32. doi: 10.2174/187231212800229255.
• Ref 2: Saint John's wort: an in vitro analysis of P-glycoprotein induction due to extended exposure. Br J Pharmacol. 2001 Dec;134(8):1601-8. doi: 10.1038/sj.bjp.0704399.
• Ref 3: Application of Intestinal Epithelial Cells Differentiated from Human Induced Pluripotent Stem Cells for Studies of Prodrug Hydrolysis and Drug Absorption in the Small Intestine. Drug Metab Dispos. 2018 Nov;46(11):1497-1506. doi: 10.1124/dmd.118.083246. Epub 2018 Aug 22.
• Ref 4: Inhibitory Effects of Commonly Used Excipients on P-Glycoprotein in Vitro. Mol Pharm. 2018 Nov 5;15(11):4835-4842. doi: 10.1021/acs.molpharmaceut.8b00482. Epub 2018 Oct 23.
• Ref 5: Characterization of the Human Intestinal Drug Transport with Ussing Chamber System Incorporating Freshly Isolated Human Jejunum. Drug Metab Dispos. 2021 Jan;49(1):84-93. doi: 10.1124/dmd.120.000138. Epub 2020 Oct 21.