General Information of Drug Combination (ID: DCIK82N)

Drug Combination Name
Carvedilol Artemisinin
Indication
Disease Entry Status REF
DD2 Investigative [1]
Component Drugs Carvedilol   DMHTEAO Artemisinin   DMOY7W3
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL
High-throughput Screening Result Testing Cell Line: DD2
Zero Interaction Potency (ZIP) Score: 2.25
Bliss Independence Score: 4
Loewe Additivity Score: 1.659
LHighest Single Agent (HSA) Score: 6.251

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Carvedilol
Disease Entry ICD 11 Status REF
Chronic heart failure BD1Z Approved [2]
Congestive heart failure BD10 Approved [3]
Pulmonary hypertension BB01 Approved [2]
Coronavirus Disease 2019 (COVID-19) 1D6Y Investigative [4]
Carvedilol Interacts with 3 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
HUAMN alpha-1 adrenergic receptor (ADRA1) TTDBOI7 ADA1A_HUMAN; ADA1B_HUMAN; ADA1D_HUMAN Inhibitor [7]
Adrenergic receptor Alpha-1 (ADRA1) TTG28O6 NOUNIPROTAC Antagonist [8]
HUMAN beta adrenergic receptor (BAR) TTJB8UY ADRB1_HUMAN; ADRB2_HUMAN; ADRB3_HUMAN Antagonist [4]
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Carvedilol Interacts with 1 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [9]
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Carvedilol Interacts with 7 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [10]
Cytochrome P450 1A2 (CYP1A2) DEJGDUW CP1A2_HUMAN Metabolism [11]
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [12]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Metabolism [13]
Cytochrome P450 2E1 (CYP2E1) DEVDYN7 CP2E1_HUMAN Metabolism [14]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [15]
UDP-glucuronosyltransferase 2B7 (UGT2B7) DEB3CV1 UD2B7_HUMAN Metabolism [12]
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⏷ Show the Full List of 7 DME(s)
Carvedilol Interacts with 28 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 2D6 (CYP2D6) OTZJC802 CP2D6_HUMAN Affects Glucuronidation [16]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Transport [17]
Beta-1 adrenergic receptor (ADRB1) OTQBWN4U ADRB1_HUMAN Increases Activity [18]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Increases Phosphorylation [19]
Epidermal growth factor receptor (EGFR) OTAPLO1S EGFR_HUMAN Increases Phosphorylation [20]
Potassium channel subfamily K member 3 (KCNK3) OTWMAV6G KCNK3_HUMAN Decreases Activity [21]
Renin (REN) OT52GZR2 RENI_HUMAN Decreases Expression [22]
Angiotensinogen (AGT) OTBZLYR3 ANGT_HUMAN Decreases Expression [23]
Transforming growth factor beta-1 proprotein (TGFB1) OTV5XHVH TGFB1_HUMAN Decreases Expression [24]
Natriuretic peptides A (NPPA) OTMQNTNX ANF_HUMAN Decreases Expression [25]
Vasopressin-neurophysin 2-copeptin (AVP) OTAVZ76K NEU2_HUMAN Decreases Expression [26]
Insulin (INS) OTZ85PDU INS_HUMAN Decreases Expression [27]
C-reactive protein (CRP) OT0RFT8F CRP_HUMAN Decreases Expression [28]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Decreases Activity [29]
Endothelin-1 (EDN1) OTZCACEG EDN1_HUMAN Decreases Expression [30]
Beta-2 adrenergic receptor (ADRB2) OTSDOX4Q ADRB2_HUMAN Increases Phosphorylation [19]
Heme oxygenase 1 (HMOX1) OTC1W6UX HMOX1_HUMAN Increases Expression [24]
Matrix metalloproteinase-9 (MMP9) OTB2QDAV MMP9_HUMAN Affects Activity [31]
Natriuretic peptides B (NPPB) OTSN2IPY ANFB_HUMAN Decreases Expression [32]
Gap junction alpha-1 protein (GJA1) OTT94MKL CXA1_HUMAN Increases Expression [33]
Interleukin-10 (IL10) OTIRFRXC IL10_HUMAN Increases Expression [34]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Increases Phosphorylation [19]
Potassium voltage-gated channel subfamily H member 2 (KCNH2) OTZX881H KCNH2_HUMAN Decreases Activity [35]
Adiponectin (ADIPOQ) OTNX23LE ADIPO_HUMAN Decreases Expression [32]
Cytochrome P450 1B1 (CYP1B1) OTYXFLSD CP1B1_HUMAN Decreases Activity [29]
Ryanodine receptor 2 (RYR2) OT0PF19E RYR2_HUMAN Increases Activity [36]
Vascular endothelial growth factor receptor 2 (KDR) OT15797V VGFR2_HUMAN Increases ADR [37]
Proto-oncogene tyrosine-protein kinase Src (SRC) OTETYX40 SRC_HUMAN Increases ADR [37]
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⏷ Show the Full List of 28 DOT(s)
Indication(s) of Artemisinin
Disease Entry ICD 11 Status REF
Malaria 1F40-1F45 Approved [5]
Artemisinin Interacts with 2 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Plasmodium Dihydroorotate dehydrogenase (Malaria DHOdehase) TT3PQ2Y PYRD_PLAF7 Inhibitor [5]
Sarcoplasmic/endoplasmic reticulum calcium ATPase (ATP2A) TTZVSJ2 NOUNIPROTAC Inhibitor [5]
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Artemisinin Interacts with 4 DME Molecule(s)
DME Name DME ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) DE4LYSA CP3A4_HUMAN Metabolism [38]
Cytochrome P450 2A6 (CYP2A6) DEJVYAZ CP2A6_HUMAN Metabolism [39]
Glutathione S-transferase alpha-1 (GSTA1) DE4ZHS1 GSTA1_HUMAN Metabolism [40]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Metabolism [38]
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Artemisinin Interacts with 10 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Glutathione S-transferase A1 (GSTA1) OTA7K5XA GSTA1_HUMAN Decreases Activity [40]
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Expression [41]
Cytochrome P450 2B6 (CYP2B6) OTOYO4S7 CP2B6_HUMAN Increases Expression [41]
Cytochrome P450 1A2 (CYP1A2) OTLLBX48 CP1A2_HUMAN Decreases Activity [42]
Cytochrome P450 2C19 (CYP2C19) OTFMJYYE CP2CJ_HUMAN Decreases Activity [42]
Glutathione S-transferase P (GSTP1) OTLP0A0Y GSTP1_HUMAN Decreases Activity [40]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Expression [41]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Activity [43]
Isocitrate dehydrogenase subunit alpha, mitochondrial (IDH3A) OT5QQB5L IDH3A_HUMAN Decreases Expression [43]
Nuclear receptor subfamily 1 group I member 3 (NR1I3) OTS3SGH7 NR1I3_HUMAN Increases Activity [44]
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⏷ Show the Full List of 10 DOT(s)

References

1 Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
2 Carvedilol FDA Label
3 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: 551).
4 Can beta-adrenergic blockers be used in the treatment of COVID-19 Med Hypotheses. 2020 May 5;142:109809.
5 The fight against drug-resistant malaria: novel plasmodial targets and antimalarial drugs. Curr Med Chem. 2008;15(2):161-71.
6 Involvement of human hepatic UGT1A1, UGT2B4, and UGT2B7 in the glucuronidation of carvedilol. Drug Metab Dispos. 2004 Feb;32(2):235-9. doi: 10.1124/dmd.32.2.235.
7 Carvedilol increases the production of interleukin-12 and interferon-gamma and improves the survival of mice infected with the encephalomyocarditis virus. J Am Coll Cardiol. 2003 Jan 15;41(2):340-5.
8 Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
9 Tarascon Pocket Pharmacopoeia 2018 Classic Shirt-Pocket Edition.
10 Role of cytochrome P450 2D6 genetic polymorphism in carvedilol hydroxylation in vitro. Drug Des Devel Ther. 2016 Jun 8;10:1909-16.
11 Pharmacokinetic interactions study between carvedilol and some antidepressants in rat liver microsomes - a comparative study. Med Pharm Rep. 2019 Apr;92(2):158-164.
12 Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab Dispos. 2004 Nov;32(11):1201-8.
13 Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
14 In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(+)- and S(-)-carvedilol. Drug Metab Dispos. 1997 Aug;25(8):970-7.
15 The role of CYP2C9 genetic polymorphism in carvedilol O-desmethylation in vitro. Eur J Drug Metab Pharmacokinet. 2016 Feb;41(1):79-86.
16 Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol. J Pharm Pharm Sci. 2006;9(1):101-12.
17 Characterization of beta-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein. Fundam Clin Pharmacol. 2006 Jun;20(3):273-82. doi: 10.1111/j.1472-8206.2006.00408.x.
18 Agonist actions of "beta-blockers" provide evidence for two agonist activation sites or conformations of the human beta1-adrenoceptor. Mol Pharmacol. 2003 Jun;63(6):1312-21. doi: 10.1124/mol.63.6.1312.
19 A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62. doi: 10.1073/pnas.0707936104. Epub 2007 Oct 9.
20 Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14555-60.
21 Carvedilol targets human K2P 3.1 (TASK1) K+ leak channels. Br J Pharmacol. 2011 Jul;163(5):1099-110. doi: 10.1111/j.1476-5381.2011.01319.x.
22 Effect of carvedilol and metoprolol on blood pressure, blood flow, and vascular resistance. J Cardiovasc Pharmacol. 1987;10 Suppl 11:S124-9.
23 Renal and cardiac function during alpha1-beta-blockade in congestive heart failure. Scand J Clin Lab Invest. 2002;62(2):97-104. doi: 10.1080/003655102753611717.
24 [Arterial hypertension and oxidative stress induced by cyclosporin. Effect of carvedilol]. Ann Ital Med Int. 2001 Apr-Jun;16(2):101-5.
25 Effects of carvedilol on atrial natriuretic peptide, catecholamines, and hemodynamics in hypertension at rest and during exercise. J Cardiovasc Pharmacol. 1992;19 Suppl 1:S90-6. doi: 10.1097/00005344-199219001-00018.
26 Lower plasma noradrenaline and blood viscosity on carvedilol vs atenolol in men with recent myocardial infarction. Blood Press. 2002;11(6):377-84. doi: 10.1080/080370502321095357.
27 After myocardial infarction carvedilol improves insulin resistance compared to metoprolol. Clin Res Cardiol. 2006 Feb;95(2):99-104. doi: 10.1007/s00392-006-0336-4. Epub 2006 Feb 6.
28 Effects of carvedilol on oxidative stress in polymorphonuclear and mononuclear cells in patients with essential hypertension. Am J Med. 2004 Apr 1;116(7):460-5. doi: 10.1016/j.amjmed.2003.10.029.
29 Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
30 Carvedilol inhibits endothelin-1 biosynthesis in cultured human coronary artery endothelial cells. J Mol Cell Cardiol. 1998 Jan;30(1):167-73. doi: 10.1006/jmcc.1997.0582.
31 Adrenoceptor blockade alters plasma gelatinase activity in patients with heart failure and MMP-9 promoter activity in a human cell line (ECV304). Pharmacol Res. 2006 Jul;54(1):57-64. doi: 10.1016/j.phrs.2006.02.006. Epub 2006 Feb 28.
32 Effect of carvedilol on plasma adiponectin concentration in patients with chronic heart failure. Circ J. 2009 Jun;73(6):1067-73. doi: 10.1253/circj.cj-08-1026. Epub 2009 Apr 14.
33 Reduced expression of endothelial connexins 43 and 37 in hypertensive rats is rectified after 7-day carvedilol treatment. Am J Hypertens. 2006 Feb;19(2):129-35. doi: 10.1016/j.amjhyper.2005.08.020.
34 Carvedilol modulates in-vitro granulocyte-macrophage colony-stimulating factor-induced interleukin-10 production in U937 cells and human monocytes. Immunol Invest. 2003 Feb;32(1-2):43-58. doi: 10.1081/imm-120019207.
35 Antiarrhythmic drug carvedilol inhibits HERG potassium channels. Cardiovasc Res. 2001 Feb 1;49(2):361-70. doi: 10.1016/s0008-6363(00)00265-0.
36 Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation. 2003 May 20;107(19):2459-66. doi: 10.1161/01.CIR.0000068316.53218.49. Epub 2003 May 12.
37 ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
38 Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol. 2005 Jun;67(6):1954-65.
39 Identification of the human cytochrome P450 enzymes involved in the in vitro metabolism of artemisinin. Br J Clin Pharmacol. 1999 Oct;48(4):528-35.
40 Inhibition of glutathione S-transferases by antimalarial drugs possible implications for circumventing anticancer drug resistance. Int J Cancer. 2002 Feb 10;97(5):700-5.
41 Antimalarial artemisinin drugs induce cytochrome P450 and MDR1 expression by activation of xenosensors pregnane X receptor and constitutive androstane receptor. Mol Pharmacol. 2005 Jun;67(6):1954-65.
42 Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
43 Identification of Compounds That Inhibit Estrogen-Related Receptor Alpha Signaling Using High-Throughput Screening Assays. Molecules. 2019 Feb 27;24(5):841. doi: 10.3390/molecules24050841.
44 In vivo and mechanistic evidence of nuclear receptor CAR induction by artemisinin. Eur J Clin Invest. 2006 Sep;36(9):647-53. doi: 10.1111/j.1365-2362.2006.01700.x.