Details of the Drug Combination

General Information of Drug Combination (ID: DC96GPZ)

Drug Combination Name
Propofol Midazolam
Indication
Disease Entry Status REF
Biliary Tract Diseases Phase 1 [1]
Component Drugs Propofol   DMB4OLE Midazolam   DMXOELT
Small molecular drug Small molecular drug
2D MOL 2D MOL
3D MOL 3D MOL

Molecular Interaction Atlas of This Drug Combination

Molecular Interaction Atlas (MIA)
Indication(s) of Propofol
Disease Entry ICD 11 Status REF
Anaesthesia 9A78.6 Approved [2]
Leukemia N.A. Approved [3]
Traumatic brain injury NA07.Z Approved [3]
Coronavirus Disease 2019 (COVID-19) 1D6Y Investigative [4]
Propofol Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Fatty acid amide hydrolase (FAAH) TTDP1UC NOUNIPROTAC Inhibitor [10]
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Propofol Interacts with 14 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]
UDP-glucuronosyltransferase 1A1 (UGT1A1) DEYGVN4 UD11_HUMAN Metabolism [13]
Cytochrome P450 2A6 (CYP2A6) DEJVYAZ CP2A6_HUMAN Metabolism [14]
Cytochrome P450 2D6 (CYP2D6) DECB0K3 CP2D6_HUMAN Metabolism [15]
Cytochrome P450 2E1 (CYP2E1) DEVDYN7 CP2E1_HUMAN Metabolism [12]
Cytochrome P450 2C18 (CYP2C18) DEZMWRE CP2CI_HUMAN Metabolism [14]
Cytochrome P450 2C8 (CYP2C8) DES5XRU CP2C8_HUMAN Metabolism [14]
Cytochrome P450 2C9 (CYP2C9) DE5IED8 CP2C9_HUMAN Metabolism [11]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Metabolism [16]
Mephenytoin 4-hydroxylase (CYP2C19) DEGTFWK CP2CJ_HUMAN Metabolism [14]
UDP-glucuronosyltransferase 1A9 (UGT1A9) DE85D2P UD19_HUMAN Metabolism [17]
UDP-glucuronosyltransferase 1A6 (UGT1A6) DESD26P UD16_HUMAN Metabolism [18]
Oleamide hydrolase 1 (FAAH) DEUM1EX FAAH1_HUMAN Metabolism [19]
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⏷ Show the Full List of 14 DME(s)
Propofol Interacts with 58 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Carbonic anhydrase 1 (CA1) OTNFBVVQ CAH1_HUMAN Decreases Activity [20]
Carbonic anhydrase 2 (CA2) OTJRMUAG CAH2_HUMAN Decreases Activity [20]
Catalase (CAT) OTHEBX9R CATA_HUMAN Decreases Activity [21]
Cellular tumor antigen p53 (TP53) OTIE1VH3 P53_HUMAN Increases Expression [21]
Cyclin-dependent kinase 1 (CDK1) OTW1SC2N CDK1_HUMAN Decreases Expression [21]
Apoptosis regulator Bcl-2 (BCL2) OT9DVHC0 BCL2_HUMAN Decreases Expression [21]
G2/mitotic-specific cyclin-B1 (CCNB1) OT19S7E5 CCNB1_HUMAN Decreases Expression [21]
G1/S-specific cyclin-D1 (CCND1) OT8HPTKJ CCND1_HUMAN Increases Expression [21]
Caspase-3 (CASP3) OTIJRBE7 CASP3_HUMAN Increases Cleavage [21]
Caspase-9 (CASP9) OTD4RFFG CASP9_HUMAN Increases Cleavage [21]
Apoptosis regulator BAX (BAX) OTAW0V4V BAX_HUMAN Increases Expression [21]
Leucine-rich colipase-like protein 1 (LRCOL1) OTDXBZF8 LRCL1_HUMAN Decreases Expression [9]
Glutamate dehydrogenase 1, mitochondrial (GLUD1) OTXKOCUH DHE3_HUMAN Decreases Expression [22]
Progonadoliberin-1 (GNRH1) OTH8A44K GON1_HUMAN Increases Expression [23]
Prolactin (PRL) OTWFQGX7 PRL_HUMAN Increases Secretion [24]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Decreases Expression [23]
Interleukin-2 receptor subunit alpha (IL2RA) OT0MWCHG IL2RA_HUMAN Decreases Secretion [25]
Fibronectin (FN1) OTB5ZN4Q FINC_HUMAN Increases Expression [23]
Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2) OTTLGRGH GNAI2_HUMAN Decreases Expression [9]
Insulin-like growth factor I (IGF1) OTIIZR61 IGF1_HUMAN Increases Expression [23]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Decreases Expression [26]
72 kDa type IV collagenase (MMP2) OT5NIWA2 MMP2_HUMAN Decreases Expression [23]
Hepatocyte growth factor receptor (MET) OT7K55MU MET_HUMAN Increases Expression [23]
Small ribosomal subunit protein uS2 (RPSA) OTJZHEGT RSSA_HUMAN Increases Expression [23]
Matrilysin (MMP7) OTVT3SEJ MMP7_HUMAN Increases Expression [23]
Solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1) OTA675TJ GTR1_HUMAN Decreases Expression [22]
Proliferating cell nuclear antigen (PCNA) OTHZ1RIA PCNA_HUMAN Decreases Expression [9]
Proto-oncogene tyrosine-protein kinase Src (SRC) OTETYX40 SRC_HUMAN Increases Expression [23]
Metalloproteinase inhibitor 2 (TIMP2) OT8S1RRP TIMP2_HUMAN Increases Expression [23]
Interleukin-10 (IL10) OTIRFRXC IL10_HUMAN Increases Expression [26]
Mitogen-activated protein kinase 3 (MAPK3) OTCYKGKO MK03_HUMAN Decreases Phosphorylation [22]
Mitogen-activated protein kinase 1 (MAPK1) OTH85PI5 MK01_HUMAN Decreases Phosphorylation [22]
Ephrin type-B receptor 2 (EPHB2) OT8VZ6C5 EPHB2_HUMAN Increases Expression [23]
3-oxo-5-alpha-steroid 4-dehydrogenase 2 (SRD5A2) OTTG0NFD S5A2_HUMAN Decreases Expression [9]
RAC-alpha serine/threonine-protein kinase (AKT1) OT8H2YY7 AKT1_HUMAN Decreases Phosphorylation [9]
Macrosialin (CD68) OTOYEY3J CD68_HUMAN Increases Expression [23]
Carbonic anhydrase 5A, mitochondrial (CA5A) OTP9M7VW CAH5A_HUMAN Decreases Expression [9]
Pigment epithelium-derived factor (SERPINF1) OTWZH98J PEDF_HUMAN Increases Expression [22]
Serine/threonine-protein kinase mTOR (MTOR) OTHH8KU7 MTOR_HUMAN Decreases Phosphorylation [9]
Proliferation marker protein Ki-67 (MKI67) OTA8N1QI KI67_HUMAN Decreases Expression [22]
Stromal cell-derived factor 1 (CXCL12) OT2QX5LL SDF1_HUMAN Decreases Expression [22]
Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN (PTEN) OTOWDUNT PTEN_HUMAN Increases Expression [9]
C-X-C chemokine receptor type 4 (CXCR4) OTUFSBX2 CXCR4_HUMAN Decreases Expression [22]
Protein SET (SET) OTGYYQJO SET_HUMAN Decreases Expression [23]
RNA-binding protein EWS (EWSR1) OT7SRHV3 EWS_HUMAN Increases Expression [23]
Alpha-1,6-mannosylglycoprotein 6-beta-N-acetylglucosaminyltransferase A (MGAT5) OTU4DD4G MGT5A_HUMAN Increases Expression [23]
Interleukin-18 (IL18) OTBB2A8O IL18_HUMAN Increases Expression [23]
Mothers against decapentaplegic homolog 2 (SMAD2) OTC6VB4K SMAD2_HUMAN Decreases Expression [23]
Hypoxia-inducible factor 1-alpha (HIF1A) OTADSC03 HIF1A_HUMAN Decreases Expression [22]
Transmembrane channel-like protein 6 (TMC6) OTKH50J4 TMC6_HUMAN Increases Expression [9]
Polycystin-1-like protein 3 (PKD1L3) OTQMYNOW PK1L3_HUMAN Decreases Expression [9]
Uncharacterized protein C10orf67, mitochondrial (C10ORF67) OTX24W0H CJ067_HUMAN Increases Expression [9]
Sodium-coupled neutral amino acid transporter 3 (SLC38A3) OTCHH25G S38A3_HUMAN Decreases Expression [9]
Oxidoreductase HTATIP2 (HTATIP2) OT9MZ4QO HTAI2_HUMAN Increases Expression [23]
Pinin (PNN) OT0HXICH PININ_HUMAN Decreases Expression [23]
Protein turtle homolog B (IGSF9B) OTNOMYYQ TUTLB_HUMAN Decreases Expression [9]
Heparanase (HPSE) OTPTK5VS HPSE_HUMAN Increases Expression [23]
Mitochondrial pyruvate carrier 1 (MPC1) OT6DYFUO MPC1_HUMAN Decreases Expression [22]
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⏷ Show the Full List of 58 DOT(s)
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 [27]
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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 [28]
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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 [29]
Cytochrome P450 4B1 (CYP4B1) DEMF740 CP4B1_HUMAN Metabolism [30]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [31]
Cytochrome P450 3A7 (CYP3A7) DERD86B CP3A7_HUMAN Metabolism [30]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Metabolism [32]
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Midazolam Interacts with 10 DOT Molecule(s)
DOT Name DOT ID UniProt ID Mode of Action REF
Cytochrome P450 3A4 (CYP3A4) OTQGYY83 CP3A4_HUMAN Increases Expression [33]
Cytochrome P450 3A5 (CYP3A5) OTSXFBXB CP3A5_HUMAN Increases Hydroxylation [34]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Expression [35]
Nuclear receptor subfamily 1 group I member 2 (NR1I2) OTC5U0N5 NR1I2_HUMAN Increases Activity [33]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [36]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Decreases Activity [37]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Increases ADR [38]
Cytochrome P450 2E1 (CYP2E1) OTHQ17JG CP2E1_HUMAN Increases Metabolism [39]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Increases ADR [38]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6) OTX4UC3O GBRA6_HUMAN Decreases Response To Substance [40]
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⏷ Show the Full List of 10 DOT(s)

Test Results of This Drug Combination in Other Disease Systems

Indication DrugCom ID Cell Line Status REF
Congenital Hydronephrosis DCNS18O N. A. Phase 4 [41]
Bronchoscopy DCFKA2J N. A. Phase 1 [42]
Anesthesia DCMLHMD N. A. Phase 1 [43]
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References

1 ClinicalTrials.gov (NCT01900938) Comparison Between Continuous Infusion and Intermittent Bolus Injection of Propofol for Deep Sedation During ERCP
2 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: 5464).
3 Propofol FDA Label
4 Propofol and sedation in patients with coronavirus disease. Am J Emerg Med. 2020 Jun 18;S0735-6757(20)30512-X.
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)
8 Effects of beta-estradiol and propofol on the 4-methylumbelliferone glucuronidation in recombinant human UGT isozymes 1A1, 1A8 and 1A9. Biopharm Drug Dispos. 2004 Nov;25(8):339-44.
9 Propofol suppresses proliferation, migration, invasion, and tumor growth of liver cancer cells via suppressing cancer susceptibility candidate 9/phosphatase and tensin homolog/AKT serine/threonine kinase/mechanistic target of rapamycin kinase axis. Hum Exp Toxicol. 2022 Jan-Dec;41:9603271211065972. doi: 10.1177/09603271211065972.
10 Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
11 Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes. Anesthesiology. 2001 Jan;94(1):110-9.
12 Inhibition of cytochrome P450 2E1 by propofol in human and porcine liver microsomes. Biochem Pharmacol. 2002 Oct 1;64(7):1151-6.
13 Substrate-dependent modulation of UDP-glucuronosyltransferase 1A1 (UGT1A1) by propofol in recombinant human UGT1A1 and human liver microsomes. Basic Clin Pharmacol Toxicol. 2007 Sep;101(3):211-4.
14 Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol. Br J Anaesth. 1998 Jun;80(6):788-95.
15 Effects of propofol on human hepatic microsomal cytochrome P450 activities. Xenobiotica. 1998 Sep;28(9):845-53.
16 Involvement of human cytochrome P450 2B6 in the omega- and 4-hydroxylation of the anesthetic agent propofol. Xenobiotica. 2007 Jul;37(7):717-24.
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 Pharmacokinetics of propofol and extrahepatic UGT1A6 gene expression in anhepatic rats. Pharmacology. 2009;84(4):219-26.
19 Update of TTD: therapeutic target database. Nucleic Acids Res. 2010 Jan;38(Database issue):D787-91.
20 Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of antioxidant phenols bioorg. Med Chem. 2009 Apr 15;17(8):3207-11.
21 Evaluation of cytotoxicity of propofol and its related mechanism in glioblastoma cells and astrocytes. Environ Toxicol. 2017 Dec;32(12):2440-2454.
22 Sevoflurane but not propofol enhances ovarian cancer cell biology through regulating cellular metabolic and signaling mechanisms. Cell Biol Toxicol. 2023 Aug;39(4):1395-1411. doi: 10.1007/s10565-022-09766-6. Epub 2022 Oct 8.
23 The differential cancer growth associated with anaesthetics in a cancer xenograft model of mice: mechanisms and implications of postoperative cancer recurrence. Cell Biol Toxicol. 2023 Aug;39(4):1561-1575. doi: 10.1007/s10565-022-09747-9. Epub 2022 Aug 12.
24 Propofol withdrawal seizures (or not). Seizure. 2008 Oct;17(7):665-7. doi: 10.1016/j.seizure.2008.03.004. Epub 2008 May 14.
25 Effects of different anaesthetic agents on immune cell function in vitro. Eur J Anaesthesiol. 2005 Aug;22(8):616-23. doi: 10.1017/s0265021505001031.
26 The effects of propofol on neutrophil function, lipid peroxidation and inflammatory response during elective coronary artery bypass grafting in patients with impaired ventricular function. Br J Anaesth. 2006 Dec;97(6):825-31. doi: 10.1093/bja/ael270. Epub 2006 Oct 9.
27 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
28 A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2009 Jan;379(1):11-26.
29 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.
30 Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
31 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.
32 Further characterization of the expression in liver and catalytic activity of CYP2B6. J Pharmacol Exp Ther. 1998 Sep;286(3):1253-9.
33 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.
34 Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab Dispos. 2004 Dec;32(12):1434-45. doi: 10.1124/dmd.104.001313. Epub 2004 Sep 21.
35 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.
36 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.
37 Association of CYP1A1 and CYP1B1 inhibition in in vitro assays with drug-induced liver injury. J Toxicol Sci. 2021;46(4):167-176. doi: 10.2131/jts.46.167.
38 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.
39 Molecular and functional characterization of drug-metabolizing enzymes and transporter expression in the novel spontaneously immortalized human hepatocyte line HC-04. Toxicol In Vitro. 2007 Dec;21(8):1390-401. doi: 10.1016/j.tiv.2007.05.003. Epub 2007 May 17.
40 GABA alpha6 receptors mediate midazolam-induced anxiolysis. J Clin Anesth. 2002 May;14(3):206-9. doi: 10.1016/s0952-8180(02)00343-4.
41 ClinicalTrials.gov (NCT02013986) Effects of Etomidate on Postoperative Circadian Rhythm Changes of Salivary Cortisol in Children
42 ClinicalTrials.gov (NCT03406533) Sedation Strategies for Diagnostic Bronchoscopy
43 ClinicalTrials.gov (NCT02536690) Remifentanil and Midazolam on Propofol for Loss of Consciousness