Details of the Drug Combination

General Information of Drug Combination (ID: DCHWZ3E)

• Drug Combination Name: Cimetidine + GSK2140944
• Indication: Infections, Bacterial; Status: Phase 1 [1]
• Component Drugs:
  Cimetidine (DMH61ZB): Small molecular drug
  GSK2140944 (DMSMFN2): N.A.

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Cimetidine

Disease Entry	ICD 11	Status	REF
Acid-reflux disorder	DA22	Approved	[2]
Gastric ulcer	DA60	Approved	[3]
Gastrinoma	2C10.1	Approved	[3]

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	[8]

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	[9]
Breast cancer resistance protein (ABCG2)	DTI7UX6	ABCG2_HUMAN	Substrate	[10]
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[11]
Multidrug and toxin extrusion protein 1 (SLC47A1)	DTZGT0P	S47A1_HUMAN	Substrate	[12]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[13]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[14]
Multidrug and toxin extrusion protein 2 (SLC47A2)	DT3TX4H	S47A2_HUMAN	Substrate	[12]

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	[15]
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Decreases Response To Substance	[16]
Broad substrate specificity ATP-binding cassette transporter ABCG2 (ABCG2)	OTW8V2V1	ABCG2_HUMAN	Affects Transport	[17]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Increases Uptake	[18]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[19]
Cytochrome P450 1A2 (CYP1A2)	OTLLBX48	CP1A2_HUMAN	Decreases Activity	[20]
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Decreases Activity	[20]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[20]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Decreases Expression	[21]
Cytochrome P450 1A1 (CYP1A1)	OTE4EFH8	CP1A1_HUMAN	Decreases Activity	[21]
Cytochrome P450 2E1 (CYP2E1)	OTHQ17JG	CP2E1_HUMAN	Decreases Expression	[21]
Glutathione S-transferase P (GSTP1)	OTLP0A0Y	GSTP1_HUMAN	Affects Expression	[21]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Activity	[21]
Aryl hydrocarbon receptor (AHR)	OTFE4EYE	AHR_HUMAN	Affects Expression	[21]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Decreases Expression	[21]
Apoptotic protease-activating factor 1 (APAF1)	OTJWIVY0	APAF_HUMAN	Increases Activity	[22]
Follitropin subunit beta (FSHB)	OTGLS283	FSHB_HUMAN	Affects Expression	[23]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Affects Expression	[23]
Gastrin (GAST)	OTD0IP9N	GAST_HUMAN	Affects Expression	[24]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Expression	[25]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Decreases Expression	[26]
Monocyte differentiation antigen CD14 (CD14)	OT83GJ47	CD14_HUMAN	Decreases Expression	[27]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[28]
Integrin alpha-4 (ITGA4)	OTSCAL0V	ITA4_HUMAN	Decreases Expression	[27]
P-selectin (SELP)	OTWR90PK	LYAM3_HUMAN	Decreases Expression	[26]
Integrin alpha-X (ITGAX)	OTOGIMHE	ITAX_HUMAN	Decreases Expression	[27]
Caspase-1 (CASP1)	OTZ3YQFU	CASP1_HUMAN	Increases Activity	[29]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[22]
Caspase-7 (CASP7)	OTAPJ040	CASP7_HUMAN	Increases Activity	[22]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[22]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[28]
Prolow-density lipoprotein receptor-related protein 1 (LRP1)	OTHTEH4G	LRP1_HUMAN	Decreases Expression	[27]
Interleukin-18 (IL18)	OTBB2A8O	IL18_HUMAN	Increases Expression	[29]
Caspase-8 (CASP8)	OTA8TVI8	CASP8_HUMAN	Increases Activity	[22]
L-lactate dehydrogenase B chain (LDHB)	OT9B1CT3	LDHB_HUMAN	Increases ADR	[7]
L-lactate dehydrogenase C chain (LDHC)	OTBX9DI5	LDHC_HUMAN	Increases ADR	[7]
Parathyroid hormone (PTH)	OTD721UF	PTHY_HUMAN	Increases ADR	[7]
Calcineurin subunit B type 1 (PPP3R1)	OTGQNFJQ	CANB1_HUMAN	Increases ADR	[7]
Solute carrier family 22 member 6 (SLC22A6)	OTKRCBVM	S22A6_HUMAN	Increases Uptake	[30]
Solute carrier family 22 member 7 (SLC22A7)	OTKTNH1W	S22A7_HUMAN	Increases Uptake	[18]
Bifunctional epoxide hydrolase 2 (EPHX2)	OTPTRCNW	HYES_HUMAN	Increases ADR	[7]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Transport	[31]

Indication(s) of GSK2140944

Disease Entry	ICD 11	Status	REF
Neisseria gonorrhoeae infection	1A7Z	Phase 3	[4]
Urinary tract infection	GC08	Phase 3	[5]
Acute bacterial skin infection	1C41	Phase 2	[6]

GSK2140944 Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
DNA topoisomerase II (TOP2)	TT0IHXV	TOP2A_HUMAN; TOP2B_HUMAN	Inhibitor	[32]

References

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• [2] 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).
• [3] Cimetidine FDA Label
• [4] ClinicalTrials.gov (NCT04010539) A Study Evaluating Efficacy and Safety of Gepotidacin Compared With Ceftriaxone Plus Azithromycin in the Treatment of Uncomplicated Urogenital Gonorrhea. U.S. National Institutes of Health.
• [5] ClinicalTrials.gov (NCT04020341) A Study to Evaluate Efficacy and Safety of Gepotidacin in the Treatment of Uncomplicated Urinary Tract Infection (UTI). U.S. National Institutes of Health.
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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• [10] Progesterone acts via progesterone receptors A and B to regulate breast cancer resistance protein expression. Mol Pharmacol. 2008 Mar;73(3):613-5.
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• [13] 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.
• [14] 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.
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• [19] 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.
• [20] Size-dependent effects of nanoparticles on the activity of cytochrome P450 isoenzymes. Toxicol Appl Pharmacol. 2010 Feb 1;242(3):326-32.
• [21] 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.
• [22] Cimetidine induces apoptosis of human salivary gland tumor cells. Oncol Rep. 2007 Mar;17(3):673-8.
• [23] Male sexual dysfunction during treatment with cimetidine. Br Med J. 1979 Mar 10;1(6164):659. doi: 10.1136/bmj.1.6164.659.
• [24] Effects of three H2-receptor antagonists (cimetidine, famotidine, ranitidine) on serum gastrin level. Int J Clin Pharmacol Res. 2002;22(2):29-35.
• [25] 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.
• [26] 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.
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• [32] Determination of disk diffusion and MIC quality control guidelines for GSK2140944, a novel bacterial type II topoisomerase inhibitor antimicrobial agent. J Clin Microbiol. 2014 Jul;52(7):2629-32.