Details of the Drug Combination

General Information of Drug Combination (ID: DCVDKWQ)

• Drug Combination Name: Fibrates + Dantrolene
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Fibrates (DMFNTMY): Small molecular drug
  Dantrolene (DM1D8XY): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 14.99
  Bliss Independence Score: 14.99
  Loewe Additivity Score: 18.62
  LHighest Single Agent (HSA) Score: 18.63

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Fibrates

Disease Entry	ICD 11	Status	REF
Dyslipidemia	5C80-5C81	Investigative	[2]

Fibrates Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Peroxisome proliferator-activated receptor alpha (PPARA)	TTJ584C	PPARA_HUMAN	Agonist	[2]

Fibrates Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Peroxisome proliferator-activated receptor alpha (PPARA)	OTK095PP	PPARA_HUMAN	Affects Binding	[8]
Cytochrome P450 2A6 (CYP2A6)	OT52TWG3	CP2A6_HUMAN	Decreases Expression	[9]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[4]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Increases Expression	[4]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Increases Expression	[10]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Expression	[11]
Retinol-binding protein 1 (RBP1)	OTRP1MFC	RET1_HUMAN	Decreases Expression	[12]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Affects Binding	[8]
Stromal cell-derived factor 1 (CXCL12)	OT2QX5LL	SDF1_HUMAN	Decreases Expression	[12]
Carnitine O-palmitoyltransferase 1, liver isoform (CPT1A)	OTI862QH	CPT1A_HUMAN	Increases Expression	[12]
Peroxisome proliferator-activated receptor delta (PPARD)	OTI4WTOP	PPARD_HUMAN	Affects Binding	[8]
Perilipin-2 (PLIN2)	OTRXJ9UN	PLIN2_HUMAN	Increases Expression	[12]
Angiopoietin-related protein 4 (ANGPTL4)	OTQL5SPX	ANGL4_HUMAN	Increases Expression	[12]

Indication(s) of Dantrolene

Disease Entry	ICD 11	Status	REF
Hyperthermia	MG26	Approved	[3]

Dantrolene Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Ryanodine receptor (RYR)	TT9YXM1	NOUNIPROTAC	Modulator	[13]

Dantrolene Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[14]

Dantrolene Interacts with 4 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Insulin-like growth factor II (IGF2)	OTJ4O6MW	IGF2_HUMAN	Decreases Response To Substance	[15]
Insulin-like growth factor I (IGF1)	OTIIZR61	IGF1_HUMAN	Decreases Response To Substance	[15]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[16]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Increases Expression	[17]

References

• [1] Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.Hepatology. 2016 Jun;63(6):1977-86. doi: 10.1002/hep.28499. Epub 2016 Mar 31.
• [2] Emerging antidyslipidemic drugs. Expert Opin Emerg Drugs. 2008 Jun;13(2):363-81.
• [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: 4172).
• [4] Comparative effects of fibrates on drug metabolizing enzymes in human hepatocytes. Pharm Res. 2005 Jan;22(1):71-8.
• [5] Complementary deoxyribonucleic acid cloning and expression of a human liver uridine diphosphate-glucuronosyltransferase glucuronidating carboxylic acid-containing drugs. J Pharmacol Exp Ther. 1993 Jan;264(1):475-9.
• [6] Gastrointestinally distributed UDP-glucuronosyltransferase 1A10, which metabolizes estrogens and nonsteroidal anti-inflammatory drugs, depends upon phosphorylation. J Biol Chem. 2004 Jul 2;279(27):28320-9. doi: 10.1074/jbc.M401396200. Epub 2004 Apr 26.
• [7] Carboxylic acid drug-induced DNA nicking in HEK293 cells expressing human UDP-glucuronosyltransferases: role of acyl glucuronide metabolites and glycation pathways. Chem Res Toxicol. 2007 Oct;20(10):1520-7. doi: 10.1021/tx700188x. Epub 2007 Sep 20.
• [8] Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. Biochem Biophys Res Commun. 2002 Jan 11;290(1):131-9. doi: 10.1006/bbrc.2001.6141.
• [9] CYP2A5/CYP2A6 expression in mouse and human hepatocytes treated with various in vivo inducers. Drug Metab Dispos. 2000 Nov;28(11):1321-6.
• [10] Expression and induction potential of cytochromes P450 in human cryopreserved hepatocytes. Drug Metab Dispos. 2005 Jul;33(7):1004-16.
• [11] Effects of fibrate compounds on expression of plasminogen activator inhibitor-1 by cultured endothelial cells. Arterioscler Thromb Vasc Biol. 1999 Jun;19(6):1577-81. doi: 10.1161/01.atv.19.6.1577.
• [12] Decrease of hepatic stellate cells in rats with enhanced sensitivity to clofibrate-induced hepatocarcinogenesis. Cancer Sci. 2011 Apr;102(4):735-41. doi: 10.1111/j.1349-7006.2011.01856.x. Epub 2011 Feb 10.
• [13] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [14] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [15] Insulin-like growth factors (IGF) I and II utilize different calcium signaling pathways in a primary human parathyroid cell culture model. World J Surg. 2006 Mar;30(3):333-45. doi: 10.1007/s00268-005-0339-8.
• [16] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [17] 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.