General Information of Drug Combination (ID: DCEP1AF)

Drug Combination Name
Palovarotene Midazolam
Indication
Disease Entry Status REF
Fibrodysplasia Ossificans Progressiva Phase 1 [1]
Component Drugs Palovarotene   DMAD2OZ 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 Palovarotene
Disease Entry ICD 11 Status REF
Fibrodysplasia ossificans progressiva FB31.1 Approved [2]
Emphysema CA21 Phase 2 [3]
Palovarotene Interacts with 1 DTT Molecule(s)
DTT Name DTT ID UniProt ID Mode of Action REF
Retinoic acid receptor gamma (RARG) TT1Q3IE RARG_HUMAN Agonist [7]
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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 [8]
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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 [9]
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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 [10]
Cytochrome P450 4B1 (CYP4B1) DEMF740 CP4B1_HUMAN Metabolism [11]
Cytochrome P450 3A5 (CYP3A5) DEIBDNY CP3A5_HUMAN Metabolism [12]
Cytochrome P450 3A7 (CYP3A7) DERD86B CP3A7_HUMAN Metabolism [11]
Cytochrome P450 2B6 (CYP2B6) DEPKLMQ CP2B6_HUMAN Metabolism [13]
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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 [14]
Cytochrome P450 3A5 (CYP3A5) OTSXFBXB CP3A5_HUMAN Increases Hydroxylation [15]
ATP-dependent translocase ABCB1 (ABCB1) OTEJROBO MDR1_HUMAN Increases Expression [16]
Nuclear receptor subfamily 1 group I member 2 (NR1I2) OTC5U0N5 NR1I2_HUMAN Increases Activity [14]
Bile salt export pump (ABCB11) OTRU7THO ABCBB_HUMAN Decreases Activity [17]
Cytochrome P450 1A1 (CYP1A1) OTE4EFH8 CP1A1_HUMAN Decreases Activity [18]
Interleukin-1 beta (IL1B) OT0DWXXB IL1B_HUMAN Increases ADR [19]
Cytochrome P450 2E1 (CYP2E1) OTHQ17JG CP2E1_HUMAN Increases Metabolism [20]
Interleukin-6 (IL6) OTUOSCCU IL6_HUMAN Increases ADR [19]
Gamma-aminobutyric acid receptor subunit alpha-6 (GABRA6) OTX4UC3O GBRA6_HUMAN Decreases Response To Substance [21]
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⏷ Show the Full List of 10 DOT(s)

References

1 ClinicalTrials.gov (NCT04829773) Study Evaluating the Effect of Food on the Pharmacokinetics of Palovarotene and the Effect of Palovarotene on the Pharmacokinetics of the CYP3A4 Substrate Midazolam in Two Cohorts of Healthy Adult Subjects
2 FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 215559
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: 8276).
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).
6 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
7 Randomised controlled trial for emphysema with a selective agonist of the gamma-type retinoic acid receptor. Eur Respir J. 2012 Aug;40(2):306-12.
8 Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
9 A novel screening strategy to identify ABCB1 substrates and inhibitors. Naunyn Schmiedebergs Arch Pharmacol. 2009 Jan;379(1):11-26.
10 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.
11 Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
12 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.
13 Further characterization of the expression in liver and catalytic activity of CYP2B6. J Pharmacol Exp Ther. 1998 Sep;286(3):1253-9.
14 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.
15 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.
16 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.
17 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.
18 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.
19 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.
20 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.
21 GABA alpha6 receptors mediate midazolam-induced anxiolysis. J Clin Anesth. 2002 May;14(3):206-9. doi: 10.1016/s0952-8180(02)00343-4.