Details of the Drug Combination

General Information of Drug Combination (ID: DCISUD6)

• Drug Combination Name: Lorazepam + Promethazine
• Indication: Peripheral Vertigo.; Status: Phase 3 [1]
• Component Drugs:
  Lorazepam (DM84ZXF): Small molecular drug
  Promethazine (DM6I5GR): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lorazepam

Disease Entry	ICD 11	Status	REF
Absence epilepsy	N.A.	Approved	[2]
Anxiety	N.A.	Approved	[2]
Anxiety disorder	6B00-6B0Z	Approved	[3]
Nausea	MD90	Approved	[2]
Panic disorder	6B01	Approved	[2]
Vomiting	MD90	Approved	[2]

Lorazepam Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Translocator protein (TSPO)	TTPTXIN	TSPO_HUMAN	Modulator	[8]

Lorazepam Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
UDP-glucuronosyltransferase 2B7 (UGT2B7)	DEB3CV1	UD2B7_HUMAN	Metabolism	[9]
UDP-glucuronosyltransferase 2B15 (UGT2B15)	DENZ6B1	UDB15_HUMAN	Metabolism	[10]

Indication(s) of Promethazine

Disease Entry	ICD 11	Status	REF
Hyperemesis gravidarum	N.A.	Approved	[4]
Nausea	MD90	Approved	[5]
Seasonal allergic rhinitis	CA08.01	Approved	[4]
Urticaria	EB00-EB05	Approved	[4]
Vasomotor/allergic rhinitis	CA08	Approved	[4]
Vomiting	MD90	Approved	[4]
Middle East Respiratory Syndrome (MERS)	1D64	Investigative	[6]
Severe acute respiratory syndrome (SARS)	1D65	Investigative	[7]

Promethazine Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
HUMAN clathrin-mediated endocytosis (RME)	TTAIY2U	N.A.	Inhibitor	[7]
Histamine H1 receptor (H1R)	TTTIBOJ	HRH1_HUMAN	Antagonist	[12]

Promethazine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[13]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[14]

Promethazine Interacts with 15 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cholinesterase (BCHE)	OTOH3WQ9	CHLE_HUMAN	Decreases Activity	[15]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[16]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Decreases Expression	[11]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[17]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[11]
Heat shock factor protein 1 (HSF1)	OTYNJ4KP	HSF1_HUMAN	Decreases Activity	[18]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[11]
Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1)	OT2YYI1A	MCL1_HUMAN	Decreases Expression	[11]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[11]
Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1)	OTXEE550	APR_HUMAN	Increases Expression	[11]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[11]
Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1)	OT15YWU7	NR3L1_HUMAN	Increases Expression	[19]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[17]
Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1)	OTY0YGT9	AMRA1_HUMAN	Decreases Expression	[11]
Autophagy protein 5 (ATG5)	OT4T5SMS	ATG5_HUMAN	Decreases Expression	[11]

References

• [1] ClinicalTrials.gov (NCT01827293) Promethazine vs. Lorazepam for Treatment of Vertigo
• [2] Lorazepam FDA Label
• [3] 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: 5884).
• [4] Promethazine 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: 7282).
• [6] Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother. 2014 Aug;58(8):4885-93.
• [7] Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov. 2020 Mar;19(3):149-150.
• [8] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [9] Pharmacokinetic and pharmacodynamic interaction of lorazepam and valproic acid in relation to UGT2B7 genetic polymorphism in healthy subjects. Clin Pharmacol Ther. 2008 Apr;83(4):595-600.
• [10] Effect of the UGT2B15 genotype on the pharmacokinetics, pharmacodynamics, and drug interactions of intravenous lorazepam in healthy volunteers. Clin Pharmacol Ther. 2005 Jun;77(6):486-94.
• [11] AMPK activation induced by promethazine increases NOXA expression and Beclin-1 phosphorylation and drives autophagy-associated apoptosis in chronic myeloid leukemia. Chem Biol Interact. 2020 Jan 5;315:108888. doi: 10.1016/j.cbi.2019.108888. Epub 2019 Nov 2.
• [12] 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.
• [13] Akathisia with combined use of midodrine and promethazine. JAMA. 2006 May 3;295(17):2000-1. Letter
• [14] Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6. Pharmacogenetics. 2003 Oct;13(10):619-26.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] A Gene Expression Biomarker Predicts Heat Shock Factor 1 Activation in a Gene Expression Compendium. Chem Res Toxicol. 2021 Jul 19;34(7):1721-1737. doi: 10.1021/acs.chemrestox.0c00510. Epub 2021 Jun 25.
• [19] Enhanced activation of human NK cells by drug-exposed hepatocytes. Arch Toxicol. 2020 Feb;94(2):439-448. doi: 10.1007/s00204-020-02668-8. Epub 2020 Feb 14.