Details of the Drug Combination

General Information of Drug Combination (ID: DCLPAJ9)

• Drug Combination Name: Diazepam + Midazolam
• Indication: Anxiety Disease; Status: Phase 1 [1]
• Component Drugs:
  Diazepam (DM08E9O): Small molecular drug
  Midazolam (DMXOELT): 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 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Aldo-keto reductase family 1 member C4 (AKR1C4)	OTW2MMOF	AK1C4_HUMAN	Decreases Activity	[20]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[20]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Activity	[20]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Decreases Activity	[20]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases Expression	[7]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[21]
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	[22]
Biglycan (BGN)	OT3AV6IF	PGS1_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]
Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2)	OTGNDWUO	GBRG2_HUMAN	Affects Response To Substance	[23]

Indication(s) of Midazolam

Disease Entry	ICD 11	Status	REF
Agitation	6A70.3	Approved	[4]
Anxiety	N.A.	Approved	[4]
Irritability	MB24	Approved	[5]
Pain	MG30-MG3Z	Approved	[4]
Traumatic brain injury	NA07.Z	Approved	[4]
Epilepsy	8A60-8A68	Phase 3	[6]

Midazolam Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Translocator protein (TSPO)	TTPTXIN	TSPO_HUMAN	Modulator	[24]

Midazolam Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[25]

Midazolam Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[26]
Cytochrome P450 4B1 (CYP4B1)	DEMF740	CP4B1_HUMAN	Metabolism	[18]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[27]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[18]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[28]

Midazolam Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Expression	[29]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[30]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[31]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Decreases Response To Substance	[32]

References

• [1] ClinicalTrials.gov (NCT03165500) Comparative Evaluation of Three Anxiety Control Protocols in Third Molar Extraction
• [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).
• [4] Midazolam 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: 3342).
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• [13] Drug Interactions Flockhart Table
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• [20] 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.
• [21] 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.
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• [23] 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.
• [24] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [25] A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2009 Jan;379(1):11-26.
• [26] Selection of alternative CYP3A4 probe substrates for clinical drug interaction studies using in vitro data and in vivo simulation. Drug Metab Dispos. 2010 Jun;38(6):981-7.
• [27] In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p450: role of cyp3a4 and cyp3a5. Drug Metab Dispos. 2003 Jul;31(7):938-44.
• [28] Further characterization of the expression in liver and catalytic activity of CYP2B6. J Pharmacol Exp Ther. 1998 Sep;286(3):1253-9.
• [29] Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol. 1996 Feb;49(2):311-8.
• [30] Benzodiazepines medazepam and midazolam are activators of pregnane X receptor and weak inducers of CYP3A4: investigation in primary cultures of human hepatocytes and hepatocarcinoma cell lines. Toxicol Lett. 2010 Mar 15;193(2):183-8.
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