Details of the Drug Combination

General Information of Drug Combination (ID: DC7RRQK)

• Drug Combination Name: Diazepam + Meperidine
• Indication: Infertility; Status: Phase 4 [1]
• Component Drugs:
  Diazepam (DM08E9O): Small molecular drug
  Meperidine (DMX4GND): 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	[6]

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	[7]

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	[8]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[9]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[10]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[11]
Cytochrome P450 2C18 (CYP2C18)	DEZMWRE	CP2CI_HUMAN	Metabolism	[12]
Cytochrome P450 2C8 (CYP2C8)	DES5XRU	CP2C8_HUMAN	Metabolism	[13]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[14]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[15]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[16]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[17]

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	[18]
Aldo-keto reductase family 1 member C4 (AKR1C4)	OTW2MMOF	AK1C4_HUMAN	Decreases Activity	[19]
Aldo-keto reductase family 1 member C3 (AKR1C3)	OTU2SXBA	AK1C3_HUMAN	Decreases Activity	[19]
Aldo-keto reductase family 1 member C2 (AKR1C2)	OTQ2XMO3	AK1C2_HUMAN	Decreases Activity	[19]
Aldo-keto reductase family 1 member C1 (AKR1C1)	OTQKR4CM	AK1C1_HUMAN	Decreases Activity	[19]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Increases Expression	[20]
Collagen alpha-1(I) chain (COL1A1)	OTI31178	CO1A1_HUMAN	Increases Expression	[5]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[21]
Integrin alpha-5 (ITGA5)	OT3RCI67	ITA5_HUMAN	Increases Expression	[5]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Increases Expression	[5]
Transforming growth factor beta-3 proprotein (TGFB3)	OT2LOUQ1	TGFB3_HUMAN	Decreases Expression	[5]
Gamma-aminobutyric acid receptor subunit alpha-1 (GABRA1)	OTC2W96H	GBRA1_HUMAN	Affects Activity	[22]
Fibroblast growth factor receptor 2 (FGFR2)	OTLOPACK	FGFR2_HUMAN	Decreases Expression	[5]
Biglycan (BGN)	OT3AV6IF	PGS1_HUMAN	Increases Expression	[5]
Integrin alpha-6 (ITGA6)	OT3FA39C	ITA6_HUMAN	Decreases Expression	[5]
Tenascin (TNC)	OTK4FSHR	TENA_HUMAN	Decreases Expression	[5]
TGF-beta receptor type-1 (TGFBR1)	OT40S1SJ	TGFR1_HUMAN	Increases Expression	[5]
TGF-beta receptor type-2 (TGFBR2)	OT3P7GZP	TGFR2_HUMAN	Increases Expression	[5]
Collagen alpha-1(VII) chain (COL7A1)	OT3MIRZJ	CO7A1_HUMAN	Decreases Expression	[5]
Transforming growth factor beta receptor type 3 (TGFBR3)	OTQOOUC4	TGBR3_HUMAN	Decreases Expression	[5]
Fibromodulin (FMOD)	OT9EJ5H8	FMOD_HUMAN	Decreases Expression	[5]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[20]
Gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2)	OTGNDWUO	GBRG2_HUMAN	Affects Response To Substance	[23]

Indication(s) of Meperidine

Disease Entry	ICD 11	Status	REF
Pain	MG30-MG3Z	Approved	[4]

Meperidine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor Alpha-2 (ADRA2)	TTQ8AFT	NOUNIPROTAC	Agonist	[24]

Meperidine 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]

Meperidine Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[26]
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[27]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[28]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[29]

References

• [1] ClinicalTrials.gov (NCT02494180) A Non-inferiority Trial on Pain Relief During Oocyte Retrieval
• [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] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Patterns of some extracellular matrix gene expression are similar in cells from cleft lip-palate patients and in human palatal fibroblasts exposed to diazepam in culture. Toxicology. 2009 Mar 4;257(1-2):10-6. doi: 10.1016/j.tox.2008.12.002. Epub 2008 Dec 9.
• [6] Translocator protein (18 kDa) mediates the pro-growth effects of diazepam on Ehrlich tumor cells in vivo. Eur J Pharmacol. 2010 Jan 25;626(2-3):131-8.
• [7] Comparative studies on in vitro methods for evaluating in vivo function of MDR1 P-glycoprotein. Pharm Res. 2001 Dec;18(12):1660-8.
• [8] Comparative study of the metabolism of drug substrates by human cytochrome P450 3A4 expressed in bacterial, yeast and human lymphoblastoid cells. Xenobiotica. 2002 Nov;32(11):937-47.
• [9] 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.
• [10] 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.
• [11] Drug Interactions Flockhart Table
• [12] 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.
• [13] 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.
• [14] Phenytoin-diazepam interaction. Ann Pharmacother. 2003 May;37(5):659-63.
• [15] Inhibitory monoclonal antibody to human cytochrome P450 2B6. Biochem Pharmacol. 1998 May 15;55(10):1633-40.
• [16] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [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.
• [22] 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.
• [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] Meperidine, remifentanil and tramadol but not sufentanil interact with alpha(2)-adrenoceptors in alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptor ... Eur J Pharmacol. 2008 Mar 17;582(1-3):70-7.
• [25] Opioids and efflux transporters. Part 3: P-glycoprotein substrate activity of 3-hydroxyl addition to meperidine analogs. Bioorg Med Chem Lett. 2008 Jun 15;18(12):3638-40.
• [26] Is meperidine the drug that just won't die? J Pediatr Pharmacol Ther. 2011 Jul;16(3):167-9.
• [27] CYP2B6, CYP3A4, and CYP2C19 are responsible for the in vitro N-demethylation of meperidine in human liver microsomes. Drug Metab Dispos. 2004 Sep;32(9):930-6.
• [28] Insights into CYP2B6-mediated drug-drug interactions. Acta Pharm Sin B. 2016 Sep;6(5):413-425.
• [29] Impact of cytochrome P450 variation on meperidine N-demethylation to the neurotoxic metabolite normeperidine. Xenobiotica. 2020 Feb;50(2):209-222.