Details of the Drug Combination

General Information of Drug Combination (ID: DCEHPCA)

• Drug Combination Name: Metoclopramide + Diphenhydramine
• Indication: Migraine; Status: Phase 1 [1]
• Component Drugs:
  Metoclopramide (DMFA5MY): Small molecular drug
  Diphenhydramine (DMKQTBA): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Metoclopramide

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

Metoclopramide Interacts with 1 DTT Molecule(s)

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

Metoclopramide Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[6]

Metoclopramide Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[7]

Metoclopramide Interacts with 11 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[8]
Retinal dehydrogenase 2 (ALDH1A2)	OTJB560Z	AL1A2_HUMAN	Decreases Expression	[9]
Lutropin subunit beta (LHB)	OT5GBOVJ	LSHB_HUMAN	Increases Expression	[10]
Prolactin (PRL)	OTWFQGX7	PRL_HUMAN	Increases Expression	[11]
Pro-glucagon (GCG)	OTXU08VF	GLUC_HUMAN	Increases Secretion	[12]
Insulin (INS)	OTZ85PDU	INS_HUMAN	Increases Expression	[13]
Gastric inhibitory polypeptide (GIP)	OTUFSTG9	GIP_HUMAN	Increases Secretion	[12]
5-hydroxytryptamine receptor 3A (HTR3A)	OTAIV1AK	5HT3A_HUMAN	Decreases Activity	[14]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[15]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Response	[16]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Increases Response	[17]

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	[18]
Histamine H1 receptor (H1R)	TTTIBOJ	HRH1_HUMAN	Antagonist	[19]

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	[20]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[21]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[22]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[22]

Diphenhydramine Interacts with 10 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cholinesterase (BCHE)	OTOH3WQ9	CHLE_HUMAN	Decreases Activity	[23]
Proepiregulin (EREG)	OTRM4NQY	EREG_HUMAN	Decreases Expression	[24]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[24]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[24]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Decreases Expression	[24]
Bone morphogenetic protein 6 (BMP6)	OT9WN536	BMP6_HUMAN	Decreases Expression	[24]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[24]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Activity	[25]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Decreases Expression	[24]
Cystine/glutamate transporter (SLC7A11)	OTKJ6PXW	XCT_HUMAN	Decreases Expression	[24]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Nausea	DCGBR5R	N. A.	Phase 1	[26]

References

• [1] ClinicalTrials.gov (NCT00682734) Metoclopramide for Migraine: A Dose Finding Study
• [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: 241).
• [3] Diphenhydramine FDA Label
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Mechanisms for metoclopramide-mediated sensitization and haloperidol-induced catalepsy in rats. Eur J Pharmacol. 2008 Jun 10;587(1-3):181-6.
• [6] 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.
• [7] Metoclopramide is metabolized by CYP2D6 and is a reversible inhibitor, but not inactivator, of CYP2D6. Xenobiotica. 2014 Apr;44(4):309-319.
• [8] Comparison of the effects of metoclopramide and domperidone on HERG channels. Pharmacology. 2005 Apr;74(1):31-6. doi: 10.1159/000083234. Epub 2005 Jan 7.
• [9] Exposure-based assessment of chemical teratogenicity using morphogenetic aggregates of human embryonic stem cells. Reprod Toxicol. 2020 Jan;91:74-91. doi: 10.1016/j.reprotox.2019.10.004. Epub 2019 Nov 8.
• [10] Differences in the opioid control of luteinizing hormone secretion between pathological and iatrogenic hyperprolactinemic states. J Clin Endocrinol Metab. 1987 Mar;64(3):508-12. doi: 10.1210/jcem-64-3-508.
• [11] Growth hormone and prolactin secretion after metoclopramide administration (DA2 receptor blockade) in fertile women. Horm Metab Res. 2001 Sep;33(9):536-9. doi: 10.1055/s-2001-17214.
• [12] Effects of metoclopramide on duodenal motility and flow events, glucose absorption, and incretin hormone release in response to intraduodenal glucose infusion. Am J Physiol Gastrointest Liver Physiol. 2010 Dec;299(6):G1326-33. doi: 10.1152/ajpgi.00476.2009. Epub 2010 Sep 9.
• [13] Effect of drugs interacting with the dopaminergic receptors on glucose levels and insulin release in healthy and type 2 diabetic subjects. Am J Ther. 2008 Jul-Aug;15(4):397-402. doi: 10.1097/MJT.0b013e318160c353.
• [14] Interactions of metoclopramide and ergotamine with human 5-HT(3A) receptors and human 5-HT reuptake carriers. Br J Pharmacol. 2005 Oct;146(4):543-52. doi: 10.1038/sj.bjp.0706351.
• [15] 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.
• [16] Association of ABCB1, 5-HT3B receptor and CYP2D6 genetic polymorphisms with ondansetron and metoclopramide antiemetic response in Indonesian cancer patients treated with highly emetogenic chemotherapy. Jpn J Clin Oncol. 2011 Oct;41(10):1168-76. doi: 10.1093/jjco/hyr117. Epub 2011 Aug 11.
• [17] Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters. J Clin Gastroenterol. 2012 Jul;46(6):494-503. doi: 10.1097/MCG.0b013e3182522624.
• [18] The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
• [19] 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.
• [20] Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos. 2007 Jan;35(1):72-8.
• [21] Pharmacogenomics in psychiatry: implications for practice. Recent Pat Biotechnol. 2014;8(2):152-9.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] ClinicalTrials.gov (NCT00475306) The Montefiore Metoclopramide Study