Details of the Drug Combination

General Information of Drug Combination (ID: DCL5NQ1)

• Drug Combination Name: Diphenhydramine + Famotidine
• Indication: Acute Cerebrovascular Accident; Status: Phase 2 [1]
• Component Drugs:
  Diphenhydramine (DMKQTBA): Small molecular drug
  Famotidine (DMRL3AB): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Diphenhydramine

Disease Entry	ICD 11	Status	REF
Hyperemesis gravidarum	N.A.	Approved	[2]
Insomnia	7A00-7A0Z	Approved	[2]
Meniere disease	AB31.0	Approved	[3]
Nausea	MD90	Approved	[2]
Seasonal allergic rhinitis	CA08.01	Approved	[2]
Vasomotor/allergic rhinitis	CA08	Approved	[2]
Vomiting	MD90	Approved	[2]

Diphenhydramine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine N-methyltransferase (HNMT)	TT2B6EV	HNMT_HUMAN	Inhibitor	[7]
Histamine H1 receptor (H1R)	TTTIBOJ	HRH1_HUMAN	Antagonist	[8]

Diphenhydramine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[9]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[10]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[11]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[11]

Diphenhydramine Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cholinesterase (BCHE)	OTOH3WQ9	CHLE_HUMAN	Decreases Activity	[12]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Decreases Expression	[13]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[13]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[13]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[13]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[13]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[13]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Activity	[14]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Decreases Expression	[13]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[13]

Indication(s) of Famotidine

Disease Entry	ICD 11	Status	REF
Gastric ulcer	DA60	Approved	[4]
Gastrinoma	2C10.1	Approved	[4]
Peptic esophagitis	N.A.	Approved	[4]
Peptic ulcer	DA61	Approved	[5]
Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 3	[6]

Famotidine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine H2 receptor (H2R)	TTQHJ1K	HRH2_HUMAN	Antagonist	[15]

Famotidine Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[16]
Organic anion transporter 1 (SLC22A6)	DTQ23VB	S22A6_HUMAN	Substrate	[17]
Organic anion transporter 3 (SLC22A8)	DTVP67E	S22A8_HUMAN	Substrate	[16]

Famotidine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[18]

Famotidine Interacts with 16 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 2 (SLC22A2)	OTGFK1AL	S22A2_HUMAN	Increases Uptake	[16]
Organic anion transporter 3 (SLC22A8)	OT8BY933	S22A8_HUMAN	Increases Uptake	[17]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Decreases Activity	[19]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[20]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[21]
Gastrin (GAST)	OTD0IP9N	GAST_HUMAN	Affects Expression	[22]
HLA class I histocompatibility antigen, alpha chain E (HLA-E)	OTX1CTFB	HLAE_HUMAN	Affects Expression	[23]
Serine/threonine-protein kinase B-raf (BRAF)	OT7S81XQ	BRAF_HUMAN	Decreases Activity	[24]
HLA class II histocompatibility antigen, DM beta chain (HLA-DMB)	OT17HGXJ	DMB_HUMAN	Affects Expression	[23]
Catenin beta-1 (CTNNB1)	OTZ932A3	CTNB1_HUMAN	Increases Expression	[25]
Fibroblast growth factor 21 (FGF21)	OT3RXVRD	FGF21_HUMAN	Increases Expression	[26]
Interleukin-3 (IL3)	OT0CQ35N	IL3_HUMAN	Increases ADR	[27]
Granulocyte-macrophage colony-stimulating factor (CSF2)	OT1M7D28	CSF2_HUMAN	Increases ADR	[27]
Solute carrier family 22 member 1 (SLC22A1)	OT7817I4	S22A1_HUMAN	Affects Transport	[19]
Thiamine transporter 2 (SLC19A3)	OTOWP1CT	S19A3_HUMAN	Increases Uptake	[28]
Granulocyte colony-stimulating factor receptor (CSF3R)	OTXRAY6X	CSF3R_HUMAN	Increases ADR	[27]

References

• [1] ClinicalTrials.gov (NCT02142712) Histamine Glutamate Antagonism in Stroke
• [2] Diphenhydramine FDA Label
• [3] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [4] Famotidine FDA Label
• [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: 7074).
• [6] ClinicalTrials.gov (NCT04370262) Multi-site Adaptive Trials Using Hydroxycholoroquine for COVID-19. U.S. National Institutes of Health.
• [7] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [8] Intact cell binding for in vitro prediction of sedative and non-sedative histamine H1-receptor antagonists based on receptor internalization. J Pharmacol Sci. 2008 May;107(1):66-79.
• [9] Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007 Jan;35(1):72-8.
• [10] Pharmacogenomics in psychiatry: implications for practice. Recent Pat Biotechnol. 2014;8(2):152-9.
• [11] 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.
• [12] Cholinesterase inhibition by phenothiazine and nonphenothiazine antihistaminics: analysis of its postulated role in synergizing organophosphate toxicity. Toxicol Appl Pharmacol. 1975 Feb;31(2):179-90.
• [13] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [14] First-generation antihistamines diphenhydramine and chlorpheniramine reverse cytokine-afforded eosinophil survival by enhancing apoptosis. Allergy Asthma Proc. 2007 Jan-Feb;28(1):79-86. doi: 10.2500/aap.2007.28.2961.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Initial 48-hour acid inhibition by intravenous infusion of omeprazole, famotidine, or both in relation to cytochrome P450 2C19 genotype status. Clin Pharmacol Ther. 2006 Nov;80(5):539-48.
• [19] Differential substrate and inhibitory activities of ranitidine and famotidine toward human organic cation transporter 1 (hOCT1; SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). J Pharmacol Exp Ther. 2005 Dec;315(3):1288-97.
• [20] Effect of common medications on the expression of SARS-CoV-2 entry receptors in liver tissue. Arch Toxicol. 2020 Dec;94(12):4037-4041. doi: 10.1007/s00204-020-02869-1. Epub 2020 Aug 17.
• [21] Hyperprolactinaemia during famotidine therapy. Lancet. 1993 Oct 2;342(8875):868. doi: 10.1016/0140-6736(93)92729-d.
• [22] Effects of three H2-receptor antagonists (cimetidine, famotidine, ranitidine) on serum gastrin level. Int J Clin Pharmacol Res. 2002;22(2):29-35.
• [23] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [24] Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010 Sep 30;467(7315):596-9. doi: 10.1038/nature09454.
• [25] Famotidine has a neuroprotective effect on MK-801 induced toxicity via the Akt/GSK-3/-catenin signaling pathway in the SH-SY5Y cell line. Chem Biol Interact. 2019 Dec 1;314:108823. doi: 10.1016/j.cbi.2019.108823. Epub 2019 Sep 26.
• [26] Increased immunoreactivity and concentration of basic fibroblast growth factor in lansoprazole-treated gastric mucosa. J Clin Gastroenterol. 1995;21 Suppl 1:S24-9.
• [27] 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.
• [28] Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3). Mol Pharm. 2015 Dec 7;12(12):4301-10.