Details of the Drug Combination

General Information of Drug Combination (ID: DCYY28M)

Drug Combination Name
Metformin Cimetidine
Indication
Disease Entry Status REF
Interaction Phase 1 [1]
Component Drugs Metformin   DM89QE1 Cimetidine   DMH61ZB
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Metformin
Disease Entry ICD 11 Status REF
Colorectal carcinoma N.A. Approved [2]
Non-insulin dependent diabetes 5A11 Approved [2]
Ovarian serous cystadenocarcinoma N.A. Approved [2]
Prostate carcinoma N.A. Approved [2]
Type-2 diabetes 5A11 Approved [3]
Coronavirus Disease 2019 (COVID-19) 1D6Y Investigative [4]
Metformin Interacts with 3 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Acetyl-CoA carboxylase 2 (ACACB) TTY84UG ACACB_HUMAN Activator [7]
Solute carrier family 47 member 1 (SLC47A1) TTMHCGA S47A1_HUMAN Modulator [8]
HUMAN mannose receptor (MRC1) TTKV8W5 MRC1_HUMAN Inhibitor [4]
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Metformin Interacts with 9 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [9]
Organic cation transporter 2 (SLC22A2) DT9IDPW S22A2_HUMAN Substrate [10]
Multidrug and toxin extrusion protein 1 (SLC47A1) DTZGT0P S47A1_HUMAN Substrate [11]
Organic cation transporter 3 (SLC22A3) DT6201N S22A3_HUMAN Substrate [12]
Organic cation transporter 1 (SLC22A1) DTT79CX S22A1_HUMAN Substrate [10]
Multidrug and toxin extrusion protein 2 (SLC47A2) DT3TX4H S47A2_HUMAN Substrate [13]
Thiamine transporter 1 (SLC19A2) DTLA4Q2 S19A2_HUMAN Substrate [14]
Thiamine transporter 2 (SLC19A3) DT39CEA S19A3_HUMAN Substrate [14]
Equilibrative nucleoside transporter 4 (SLC29A4) DT3EAQP S29A4_HUMAN Substrate [15]
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⏷ Show the Full List of 9 DTP(s)
Indication(s) of Cimetidine
Disease Entry ICD 11 Status REF
Acid-reflux disorder DA22 Approved [5]
Gastric ulcer DA60 Approved [6]
Gastrinoma 2C10.1 Approved [6]
Cimetidine Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Histamine H2 receptor (H2R) TTQHJ1K HRH2_HUMAN Antagonist [17]
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Cimetidine Interacts with 7 DTP Molecule(s)
DTP Name DTP ID UniProt ID Mode of Action REF
P-glycoprotein 1 (ABCB1) DTUGYRD MDR1_HUMAN Substrate [18]
Breast cancer resistance protein (ABCG2) DTI7UX6 ABCG2_HUMAN Substrate [19]
Organic cation transporter 2 (SLC22A2) DT9IDPW S22A2_HUMAN Substrate [20]
Multidrug and toxin extrusion protein 1 (SLC47A1) DTZGT0P S47A1_HUMAN Substrate [13]
Organic cation transporter 1 (SLC22A1) DTT79CX S22A1_HUMAN Substrate [21]
Organic anion transporter 3 (SLC22A8) DTVP67E S22A8_HUMAN Substrate [22]
Multidrug and toxin extrusion protein 2 (SLC47A2) DT3TX4H S47A2_HUMAN Substrate [13]
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⏷ Show the Full List of 7 DTP(s)
Cimetidine Interacts with 42 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Multidrug and toxin extrusion protein 1 (SLC47A1) OTZX0U5Q S47A1_HUMAN Decreases Activity [23]
Solute carrier family 22 member 2 (SLC22A2) OTGFK1AL S22A2_HUMAN Decreases Response To Substance [24]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2) OTW8V2V1 ABCG2_HUMAN Affects Transport [25]
Organic anion transporter 3 (SLC22A8) OT8BY933 S22A8_HUMAN Increases Uptake [26]
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Decreases Activity [27]
Cytochrome P450 1A2 (CYP1A2) OTLLBX48 CP1A2_HUMAN Decreases Activity [28]
Cytochrome P450 2D6 (CYP2D6) OTZJC802 CP2D6_HUMAN Decreases Activity [28]
Cytochrome P450 2C9 (CYP2C9) OTGLBN29 CP2C9_HUMAN Decreases Activity [28]
Nuclear receptor subfamily 1 group I member 2 (NR1I2) OTC5U0N5 NR1I2_HUMAN Decreases Expression [29]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Decreases Activity [29]
Cytochrome P450 2E1 (CYP2E1) OTHQ17JG CP2E1_HUMAN Decreases Expression [29]
Glutathione S-transferase P (GSTP1) OTLP0A0Y GSTP1_HUMAN Affects Expression [29]
Cytochrome P450 2B6 (CYP2B6) OTOYO4S7 CP2B6_HUMAN Decreases Activity [29]
Aryl hydrocarbon receptor (AHR) OTFE4EYE AHR_HUMAN Affects Expression [29]
Nuclear receptor subfamily 1 group I member 3 (NR1I3) OTS3SGH7 NR1I3_HUMAN Decreases Expression [29]
Apoptotic protease-activating factor 1 (APAF1) OTJWIVY0 APAF_HUMAN Increases Activity [30]
Follitropin subunit beta (FSHB) OTGLS283 FSHB_HUMAN Affects Expression [31]
Prolactin (PRL) OTWFQGX7 PRL_HUMAN Affects Expression [31]
Gastrin (GAST) OTD0IP9N GAST_HUMAN Affects Expression [32]
Interferon gamma (IFNG) OTXG9JM7 IFNG_HUMAN Increases Expression [33]
Intercellular adhesion molecule 1 (ICAM1) OTTOIX77 ICAM1_HUMAN Decreases Expression [34]
Monocyte differentiation antigen CD14 (CD14) OT83GJ47 CD14_HUMAN Decreases Expression [35]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [36]
Integrin alpha-4 (ITGA4) OTSCAL0V ITA4_HUMAN Decreases Expression [35]
P-selectin (SELP) OTWR90PK LYAM3_HUMAN Decreases Expression [34]
Integrin alpha-X (ITGAX) OTOGIMHE ITAX_HUMAN Decreases Expression [35]
Caspase-1 (CASP1) OTZ3YQFU CASP1_HUMAN Increases Activity [37]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Activity [30]
Caspase-7 (CASP7) OTAPJ040 CASP7_HUMAN Increases Activity [30]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Activity [30]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [36]
Prolow-density lipoprotein receptor-related protein 1 (LRP1) OTHTEH4G LRP1_HUMAN Decreases Expression [35]
Interleukin-18 (IL18) OTBB2A8O IL18_HUMAN Increases Expression [37]
Caspase-8 (CASP8) OTA8TVI8 CASP8_HUMAN Increases Activity [30]
L-lactate dehydrogenase B chain (LDHB) OT9B1CT3 LDHB_HUMAN Increases ADR [16]
L-lactate dehydrogenase C chain (LDHC) OTBX9DI5 LDHC_HUMAN Increases ADR [16]
Parathyroid hormone (PTH) OTD721UF PTHY_HUMAN Increases ADR [16]
Calcineurin subunit B type 1 (PPP3R1) OTGQNFJQ CANB1_HUMAN Increases ADR [16]
Solute carrier family 22 member 6 (SLC22A6) OTKRCBVM S22A6_HUMAN Increases Uptake [38]
Solute carrier family 22 member 7 (SLC22A7) OTKTNH1W S22A7_HUMAN Increases Uptake [26]
Bifunctional epoxide hydrolase 2 (EPHX2) OTPTRCNW HYES_HUMAN Increases ADR [16]
Solute carrier family 22 member 3 (SLC22A3) OTQYGVXX S22A3_HUMAN Increases Transport [39]
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⏷ Show the Full List of 42 DOT(s)

References

1 ClinicalTrials.gov (NCT05365451) Pharmacokinetic Drug-Drug Interaction Study to Identify Biomarkers of Kidney Transporters
2 Metformin FDA Label
3 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
4 A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing. March 2020
5 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: 1231).
6 Cimetidine FDA Label
7 AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C. Biochem Pharmacol. 2009 Jun 1;77(11):1684-93.
8 Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006 Aug;23(8):1696-701.
9 Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin. Am J Obstet Gynecol. 2010 Apr;202(4):383.e1-7.
10 Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab Pharmacokinet. 2005 Oct;20(5):379-86.
11 Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol. 2010 Apr;298(4):F997-F1005.
12 Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology. 2009 Oct;50(4):1227-40.
13 Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H(+)-organic cation antiporters. Biochem Pharmacol. 2007 Jul 15;74(2):359-71.
14 Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Mol Pharm. 2015 Dec 7;12(12):4301-10.
15 Metformin: from mechanisms of action to therapies. Cell Metab. 2014 Dec 2;20(6):953-66.
16 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.
17 Histamine H1 and H2 receptor antagonists accelerate skin barrier repair and prevent epidermal hyperplasia induced by barrier disruption in a dry environment. J Invest Dermatol. 2001 Feb;116(2):261-5.
18 Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade. Cancer Lett. 2016 Jan 1;370(1):153-64.
19 Progesterone acts via progesterone receptors A and B to regulate breast cancer resistance protein expression. Mol Pharmacol. 2008 Mar;73(3):613-5.
20 Elevated systemic elimination of cimetidine in rats with acute biliary obstruction: the role of renal organic cation transporter OCT2. Drug Metab Pharmacokinet. 2010;25(4):328-34.
21 Identification of novel substrates and structure-activity relationship of cellular uptake mediated by human organic cation transporters 1 and 2. J Med Chem. 2013 Sep 26;56(18):7232-42.
22 Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther. 2007 May;321(2):673-83.
23 Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab Dispos. 2006 Nov;34(11):1868-74. doi: 10.1124/dmd.106.010876. Epub 2006 Aug 23.
24 Ameliorative effects of SLC22A2 gene polymorphism 808 G/T and cimetidine on cisplatin-induced nephrotoxicity in Chinese cancer patients. Food Chem Toxicol. 2012 Jul;50(7):2289-93. doi: 10.1016/j.fct.2012.03.077. Epub 2012 Apr 16.
25 Human breast cancer resistance protein: interactions with steroid drugs, hormones, the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and transport of cimetidine. J Pharmacol Exp Ther. 2005 Jan;312(1):144-52. doi: 10.1124/jpet.104.073916. Epub 2004 Sep 13.
26 A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters. J Pharmacol Exp Ther. 2005 Oct;315(1):337-45.
27 Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA and UK). Eur J Clin Pharmacol. 2005 Aug;61(7):531-6.
28 Size-dependent effects of nanoparticles on the activity of cytochrome P450 isoenzymes. Toxicol Appl Pharmacol. 2010 Feb 1;242(3):326-32.
29 Expression and inducibility of cytochrome P450s (CYP1A1, 2B6, 2E1, 3A4) in human cord blood CD34(+) stem cell-derived differentiating neuronal cells. Toxicol Sci. 2012 Oct;129(2):392-410.
30 Cimetidine induces apoptosis of human salivary gland tumor cells. Oncol Rep. 2007 Mar;17(3):673-8.
31 Male sexual dysfunction during treatment with cimetidine. Br Med J. 1979 Mar 10;1(6164):659. doi: 10.1136/bmj.1.6164.659.
32 Effects of three H2-receptor antagonists (cimetidine, famotidine, ranitidine) on serum gastrin level. Int J Clin Pharmacol Res. 2002;22(2):29-35.
33 Histamine and histamine-receptor antagonists modify gene expression and biosynthesis of interferon gamma in peripheral human blood mononuclear cells and in CD19-depleted cell subsets. Immunol Lett. 1999 Nov 1;70(2):95-9. doi: 10.1016/s0165-2478(99)00126-1.
34 Effects of histamine 2 receptor antagonists on endothelial-neutrophil adhesion and surface expression of endothelial adhesion molecules induced by high glucose levels. J Diabetes Complications. 2007 Jan-Feb;21(1):50-5. doi: 10.1016/j.jdiacomp.2006.02.002.
35 Increased histidine decarboxylase expression during in vitro monocyte maturation; a possible role of endogenously synthesised histamine in monocyte/macrophage differentiation. Inflamm Res. 2001 Aug;50(8):428-34. doi: 10.1007/PL00000266.
36 Cimetidine induces apoptosis in gastric cancer cells in vitro and inhibits tumor growth in vivo. Oncol Rep. 2010 Mar;23(3):693-700. doi: 10.3892/or_00000686.
37 Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes. Mol Pharmacol. 2006 Aug;70(2):450-3. doi: 10.1124/mol.106.025890. Epub 2006 May 24.
38 Different transport properties between famotidine and cimetidine by human renal organic ion transporters (SLC22A). Eur J Pharmacol. 2004 Oct 25;503(1-3):25-30.
39 Caki-1 cells as a model system for the interaction of renally secreted drugs with OCT3. Nephron Physiol. 2008;108(2):p18-28. doi: 10.1159/000115040. Epub 2008 Feb 4.