Details of the Drug Combination

General Information of Drug Combination (ID: DCOCUWU)

• Drug Combination Name: Lidocaine + Midazolam
• Indication: Critical Illness; Status: Phase 4 [1]
• Component Drugs:
  Lidocaine (DML4ZOT): Small molecular drug
  Midazolam (DMXOELT): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Lidocaine

Disease Entry	ICD 11	Status	REF
Anaesthesia	9A78.6	Approved	[2]
Carpal tunnel syndrome	N.A.	Approved	[3]
Interstitial cystitis	GC00.3	Approved	[3]
Long QT syndrome	BC65.0	Approved	[3]
Pain	MG30-MG3Z	Approved	[3]
Pediculus capitis infestation	1G00.0	Approved	[3]
Periodontitis	DA0C	Approved	[3]
Postherpetic neuralgia	1E91.5	Approved	[3]
Pthirus pubis infestation	N.A.	Approved	[3]
Dysmenorrhea	GA34.3	Phase 2	[4]
Chronic pain	MG30	Investigative	[3]
Neuralgia	N.A.	Investigative	[3]
Premature ejaculation	HA03.0Z	Investigative	[3]
Pruritus	EC90	Investigative	[3]

Lidocaine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Voltage-gated sodium channel alpha Nav1.9 (SCN11A)	TTN9VTF	SCNBA_HUMAN	Blocker	[9]

Lidocaine Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[10]

Lidocaine Interacts with 10 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[11]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[12]
Cytochrome P450 2A6 (CYP2A6)	DEJVYAZ	CP2A6_HUMAN	Metabolism	[13]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[14]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[15]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[15]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[13]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[13]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[16]

Lidocaine Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Alpha-1-acid glycoprotein 1 (ORM1)	OTZKSBRE	A1AG1_HUMAN	Affects Binding	[17]
C-reactive protein (CRP)	OT0RFT8F	CRP_HUMAN	Increases ADR	[18]
Alkaline phosphatase, placental type (ALPP)	OTZU4G9W	PPB1_HUMAN	Increases ADR	[18]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[19]
Neurofilament medium polypeptide (NEFM)	OT8VCBNF	NFM_HUMAN	Decreases Expression	[8]
Alpha-1-acid glycoprotein 2 (ORM2)	OTRJGZP8	A1AG2_HUMAN	Affects Binding	[17]
Neuronatin (NNAT)	OTNRLO7G	NNAT_HUMAN	Decreases Expression	[8]
Transient receptor potential cation channel subfamily V member 1 (TRPV1)	OTHHDR03	TRPV1_HUMAN	Increases Activity	[20]
Sodium channel protein type 5 subunit alpha (SCN5A)	OTGYZWR6	SCN5A_HUMAN	Affects Response To Substance	[21]

Indication(s) of Midazolam

Disease Entry	ICD 11	Status	REF
Agitation	6A70.3	Approved	[5]
Anxiety	N.A.	Approved	[5]
Irritability	MB24	Approved	[6]
Pain	MG30-MG3Z	Approved	[5]
Traumatic brain injury	NA07.Z	Approved	[5]
Epilepsy	8A60-8A68	Phase 3	[7]

Midazolam Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Translocator protein (TSPO)	TTPTXIN	TSPO_HUMAN	Modulator	[22]

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	[23]

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	[24]
Cytochrome P450 4B1 (CYP4B1)	DEMF740	CP4B1_HUMAN	Metabolism	[13]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[25]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[13]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[26]

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	[27]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Increases Activity	[28]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[29]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6)	OTX4UC3O	GBRA6_HUMAN	Decreases Response To Substance	[30]

Test Results of This Drug Combination in Other Disease Systems

Indication	DrugCom ID	Cell Line	Status	REF
Sedation, Conscious	DCPKYRT	N. A.	Phase 4	[31]

References

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• [3] Lidocaine FDA Label
• [4] ClinicalTrials.gov (NCT00651313) Efficacy and Safety Study of Lidocaine Vaginal Gel for Recurrent Dysmenorrhea (Painful Periods). U.S. National Institutes of Health.
• [5] Midazolam FDA Label
• [6] 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).
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
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• [15] Drug Interactions Flockhart Table
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• [17] Binding of disopyramide, methadone, dipyridamole, chlorpromazine, lignocaine and progesterone to the two main genetic variants of human alpha 1-acid glycoprotein: evidence for drug-binding differences between the variants and for the presence of two separate drug-binding sites on alpha 1-acid glycoprotein. Pharmacogenetics. 1996 Oct;6(5):403-15. doi: 10.1097/00008571-199610000-00004.
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• [21] Lidocaine-induced Brugada syndrome phenotype linked to a novel double mutation in the cardiac sodium channel. Circ Res. 2008 Aug 15;103(4):396-404. doi: 10.1161/CIRCRESAHA.108.172619. Epub 2008 Jul 3.
• [22] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [23] A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2009 Jan;379(1):11-26.
• [24] 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.
• [25] 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.
• [26] Further characterization of the expression in liver and catalytic activity of CYP2B6. J Pharmacol Exp Ther. 1998 Sep;286(3):1253-9.
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• [28] 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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• [31] ClinicalTrials.gov (NCT02314546) Intranasal Midazolam in Children as a Pre-Operative Sedative