Details of the Drug Combination

General Information of Drug Combination (ID: DC6TK39)

• Drug Combination Name: Diazepam + Cinnarizine
• Indication: Methamphetamine-induced Psychosis; Status: Phase 4 [1]
• Component Drugs:
  Diazepam (DM08E9O): Small molecular drug
  Cinnarizine (DM7U5QJ): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Diazepam

Disease Entry	ICD 11	Status	REF
Alcohol withdrawal	N.A.	Approved	[2]
Alcohol withdrawal delirium	N.A.	Approved	[2]
Anxiety	N.A.	Approved	[2]
Epilepsy	8A60-8A68	Approved	[3]
Tetanus	1C13	Investigative	[2]

Diazepam Interacts with 1 DTT Molecule(s)

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

Diazepam Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[9]

Diazepam Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[10]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[11]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[12]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[13]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[14]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[15]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[16]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[17]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[18]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[19]

Diazepam Interacts with 23 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Translocator protein (TSPO)	OTSU7ESK	TSPO_HUMAN	Increases ADR	[20]
Aldo-keto reductase family 1 member C4 (AKR1C4)	OTW2MMOF	AK1C4_HUMAN	Decreases Activity	[21]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[21]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Activity	[21]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Decreases Activity	[21]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[22]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases Expression	[7]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[23]
Integrin alpha-5 (ITGA5)	OT3RCI67	ITA5_HUMAN	Increases Expression	[7]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Increases Expression	[7]
Transforming growth factor beta-3 proprotein (TGFB3)	OT2LOUQ1	TGFB3_HUMAN	Decreases Expression	[7]
Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1)	OTC2W96H	GBRA1_HUMAN	Affects Activity	[24]
Fibroblast growth factor receptor 2 (FGFR2)	OTLOPACK	FGFR2_HUMAN	Decreases Expression	[7]
Biglycan (BGN)	OT3AV6IF	PGS1_HUMAN	Increases Expression	[7]
Integrin alpha-6 (ITGA6)	OT3FA39C	ITA6_HUMAN	Decreases Expression	[7]
Tenascin (TNC)	OTK4FSHR	TENA_HUMAN	Decreases Expression	[7]
TGF-beta receptor type-1 (TGFBR1)	OT40S1SJ	TGFR1_HUMAN	Increases Expression	[7]
TGF-beta receptor type-2 (TGFBR2)	OT3P7GZP	TGFR2_HUMAN	Increases Expression	[7]
Collagen alpha-1(VII) chain (COL7A1)	OT3MIRZJ	CO7A1_HUMAN	Decreases Expression	[7]
Transforming growth factor beta receptor type 3 (TGFBR3)	OTQOOUC4	TGBR3_HUMAN	Decreases Expression	[7]
Fibromodulin (FMOD)	OT9EJ5H8	FMOD_HUMAN	Decreases Expression	[7]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[22]
Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2)	OTGNDWUO	GBRG2_HUMAN	Affects Response To Substance	[25]

Indication(s) of Cinnarizine

Disease Entry	ICD 11	Status	REF
Meniere disease	AB31.0	Approved	[4]
Nausea	MD90	Approved	[5]
Vertigo meniere disease	AB31.0	Approved	[6]

Cinnarizine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Histamine H1 receptor (H1R)	TTTIBOJ	HRH1_HUMAN	Antagonist	[26]

Cinnarizine Interacts with 6 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[27]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[28]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[19]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[19]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[19]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[19]

Cinnarizine Interacts with 1 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[29]

References

• [1] ClinicalTrials.gov (NCT01939093) Therapeutic Effect of Quetiapine on Methamphetamine-Induced Psychosis
• [2] Diazepam 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: 3364).
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• [6] Drug information of Cinnarizine, 2008. eduDrugs.
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• [9] Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
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• [11] In vitro metabolism of zolmitriptan in rat cytochromes induced with beta-naphthoflavone and the interaction between six drugs and zolmitriptan. Chem Biol Interact. 2003 Dec 15;146(3):263-72.
• [12] Eight inhibitory monoclonal antibodies define the role of individual P-450s in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism. Drug Metab Dispos. 1999 Jan;27(1):102-9.
• [13] Drug Interactions Flockhart Table
• [14] Targeted antipeptide antibodies to cytochrome P450 2C18 based on epitope mapping of an inhibitory monoclonal antibody to P450 2C51. Arch Biochem Biophys. 1997 Feb 15;338(2):157-64.
• [15] Use of inhibitory monoclonal antibodies to assess the contribution of cytochromes P450 to human drug metabolism. Eur J Pharmacol. 2000 Apr 14;394(2-3):199-209.
• [16] Phenytoin-diazepam interaction. Ann Pharmacother. 2003 May;37(5):659-63.
• [17] Inhibitory monoclonal antibody to human cytochrome P450 2B6. Biochem Pharmacol. 1998 May 15;55(10):1633-40.
• [18] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [19] 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.
• [20] 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.
• [21] Substrate specificity of human 3(20)alpha-hydroxysteroid dehydrogenase for neurosteroids and its inhibition by benzodiazepines. Biol Pharm Bull. 2002 Apr;25(4):441-5.
• [22] 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.
• [23] The three recombinant domains of human serum albumin. Structural characterization and ligand binding properties. J Biol Chem. 1999 Oct 8;274(41):29303-10. doi: 10.1074/jbc.274.41.29303.
• [24] GABAergic dysfunction in schizophrenia: new treatment strategies on the horizon. Psychopharmacology (Berl). 2005 Jul;180(2):191-205. doi: 10.1007/s00213-005-2212-8. Epub 2005 Apr 28.
• [25] Heterogeneity of GABA(A) receptor-mediated responses in the human IMR-32 neuroblastoma cell line. J Neurosci Res. 2000 May 15;60(4):504-10. doi: 10.1002/(SICI)1097-4547(20000515)60:4<504::AID-JNR9>3.0.CO;2-Y.
• [26] Central effects of cinnarizine: restricted use in aircrew. Aviat Space Environ Med. 2002 Jun;73(6):570-4.
• [27] Integrated analysis on the physicochemical properties of dihydropyridine calcium channel blockers in grapefruit juice interactions. Curr Pharm Biotechnol. 2012 Jul;13(9):1705-17.
• [28] Insights into the substrate specificity, inhibitors, regulation, and polymorphisms and the clinical impact of human cytochrome P450 1A2. AAPS J. 2009 Sep;11(3):481-94.
• [29] Interference with bile salt export pump function is a susceptibility factor for human liver injury in drug development. Toxicol Sci. 2010 Dec; 118(2):485-500.