Details of the Drug Combination

General Information of Drug Combination (ID: DC9CI6E)

• Drug Combination Name: Droperidol + Diphenhydramine
• Indication: Cannabis Hyperemesis Syndrome; Status: Phase 3 [1]
• Component Drugs:
  Droperidol (DM0DXA8): Small molecular drug
  Diphenhydramine (DMKQTBA): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Droperidol

Disease Entry	ICD 11	Status	REF
Nausea	MD90	Approved	[2]

Droperidol Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Dopamine D2 receptor (D2R)	TTEX248	DRD2_HUMAN	Binder	[5]

Droperidol Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Increases ADR	[6]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[7]
D(3) dopamine receptor (DRD3)	OT0OFFKB	DRD3_HUMAN	Increases ADR	[6]
D(4) dopamine receptor (DRD4)	OTAJTO7N	DRD4_HUMAN	Increases ADR	[6]

Indication(s) of Diphenhydramine

Disease Entry	ICD 11	Status	REF
Hyperemesis gravidarum	N.A.	Approved	[3]
Insomnia	7A00-7A0Z	Approved	[3]
Meniere disease	AB31.0	Approved	[4]
Nausea	MD90	Approved	[3]
Seasonal allergic rhinitis	CA08.01	Approved	[3]
Vasomotor/allergic rhinitis	CA08	Approved	[3]
Vomiting	MD90	Approved	[3]

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	[8]
Histamine H1 receptor (H1R)	TTTIBOJ	HRH1_HUMAN	Antagonist	[9]

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	[10]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[11]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[12]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[12]

Diphenhydramine Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cholinesterase (BCHE)	OTOH3WQ9	CHLE_HUMAN	Decreases Activity	[13]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Decreases Expression	[14]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[14]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[14]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[14]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[14]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[14]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Activity	[15]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Decreases Expression	[14]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[14]

References

• [1] ClinicalTrials.gov (NCT05244460) Droperidol on Prevention of Cannabis Hyperemesis Syndrome
• [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: 7172).
• [3] Diphenhydramine FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Alpha-adrenergic blockade: a possible mechanism of tocolytic action of certain benzodiazepines in a postpartum rat model in vivo. Life Sci. 2003 Jan 24;72(10):1093-102.
• [6] 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.
• [7] Safety pharmacology assessment of drug-induced QT-prolongation in dogs with reduced repolarization reserve. J Pharmacol Toxicol Methods. 2006 Sep-Oct;54(2):130-40. doi: 10.1016/j.vascn.2006.03.011. Epub 2006 Apr 25.
• [8] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [9] 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.
• [10] Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007 Jan;35(1):72-8.
• [11] Pharmacogenomics in psychiatry: implications for practice. Recent Pat Biotechnol. 2014;8(2):152-9.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] 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.