Details of the Drug Combination

General Information of Drug Combination (ID: DCBQAEL)

• Drug Combination Name: Efavirenz + Bosentan
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Efavirenz (DMC0GSJ): Small molecular drug
  Bosentan (DMIOGBU): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 35.56
  Bliss Independence Score: 35.56
  Loewe Additivity Score: 50.11
  LHighest Single Agent (HSA) Score: 50.11

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Efavirenz

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[2]

Efavirenz Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Reverse transcriptase (HIV RT)	TT84ETX	POL_HV1B1	Modulator	[5]

Efavirenz Interacts with 2 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[6]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[7]

Efavirenz Interacts with 3 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 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[10]

Efavirenz Interacts with 21 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[11]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[12]
Dynamin-1-like protein (DNM1L)	OTXK1Q1G	DNM1L_HUMAN	Affects Localization	[13]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[14]
Dynamin-like 120 kDa protein, mitochondrial (OPA1)	OTJGNWPW	OPA1_HUMAN	Increases Expression	[13]
Mitofusin-2 (MFN2)	OTPYN8A3	MFN2_HUMAN	Increases Expression	[13]
Thyroglobulin (TG)	OT3ELHIJ	THYG_HUMAN	Increases Expression	[15]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[16]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Secretion	[17]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[14]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[17]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[17]
Calnexin (CANX)	OTYP1F6J	CALX_HUMAN	Affects Localization	[13]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[13]
Lon protease homolog, mitochondrial (LONP1)	OT665WYT	LONM_HUMAN	Increases Expression	[13]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[14]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[17]
Regulator of microtubule dynamics protein 3 (RMDN3)	OTKO7AUM	RMD3_HUMAN	Increases Expression	[13]
Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)	OTQR6ENW	M3K5_HUMAN	Increases Phosphorylation	[14]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Expression	[13]
Mitochondrial fission 1 protein (FIS1)	OT2HL10J	FIS1_HUMAN	Increases Expression	[13]

Indication(s) of Bosentan

Disease Entry	ICD 11	Status	REF
Pulmonary arterial hypertension	BB01.0	Approved	[3]
Pulmonary hypertension	BB01	Approved	[4]
Scleroderma	4A42	Investigative	[4]

Bosentan Interacts with 2 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Endothelin A receptor (EDNRA)	TTKRD0G	EDNRA_HUMAN	Modulator	[5]
Endothelin B receptor (EDNRB)	TT3ZTGU	EDNRB_HUMAN	Modulator	[5]

Bosentan Interacts with 3 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1B1 (SLCO1B1)	DT3D8F0	SO1B1_HUMAN	Substrate	[19]
Organic anion transporting polypeptide 1B3 (SLCO1B3)	DT9C1TS	SO1B3_HUMAN	Substrate	[19]
Organic anion transporting polypeptide 2B1 (SLCO2B1)	DTPFTEQ	SO2B1_HUMAN	Substrate	[19]

Bosentan Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[20]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[21]

Bosentan Interacts with 40 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Expression	[18]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Expression	[18]
Serine/threonine-protein kinase DCLK1 (DCLK1)	OTVSPS98	DCLK1_HUMAN	Affects Expression	[18]
Kynurenine 3-monooxygenase (KMO)	OT3MRMM9	KMO_HUMAN	Affects Expression	[18]
Carbonic anhydrase 12 (CA12)	OT6WNFU8	CAH12_HUMAN	Affects Expression	[18]
All-trans-retinol dehydrogenase ADH1B (ADH1B)	OTV3TB81	ADH1B_HUMAN	Decreases Expression	[18]
Alcohol dehydrogenase 1C (ADH1C)	OTO1DV7F	ADH1G_HUMAN	Decreases Expression	[18]
Complement component C9 (C9)	OT7I5FDX	CO9_HUMAN	Affects Expression	[18]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[18]
Fructose-bisphosphate aldolase B (ALDOB)	OT7FR69A	ALDOB_HUMAN	Decreases Expression	[18]
Amino acid transporter heavy chain SLC3A2 (SLC3A2)	OTBR33M9	4F2_HUMAN	Increases Expression	[18]
All-trans-retinol dehydrogenase ADH4 (ADH4)	OTKDKKNG	ADH4_HUMAN	Decreases Expression	[18]
Glutathione S-transferase theta-2 (GSTT2)	OTANW3TJ	GST2_HUMAN	Decreases Expression	[18]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[18]
3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1 (HSD3B1)	OTNAZVKB	3BHS1_HUMAN	Affects Expression	[18]
Tyrosine aminotransferase (TAT)	OT2CJ91O	ATTY_HUMAN	Affects Expression	[18]
Phosphatidylcholine translocator ABCB4 (ABCB4)	OTE6PY83	MDR3_HUMAN	Decreases Expression	[18]
Macrophage mannose receptor 1 (MRC1)	OTTVCOPT	MRC1_HUMAN	Affects Expression	[18]
G0/G1 switch protein 2 (G0S2)	OT8FL49L	G0S2_HUMAN	Affects Expression	[18]
Carbamoyl-phosphate synthase , mitochondrial (CPS1)	OTXV8NSR	CPSM_HUMAN	Decreases Expression	[18]
Glucose-6-phosphatase catalytic subunit 1 (G6PC1)	OTJ6FM9F	G6PC1_HUMAN	Affects Expression	[18]
Achaete-scute homolog 1 (ASCL1)	OTI4X44G	ASCL1_HUMAN	Affects Expression	[18]
Microsomal triglyceride transfer protein large subunit (MTTP)	OTNUVSDT	MTP_HUMAN	Decreases Expression	[18]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Affects Expression	[18]
Metallothionein-1X (MT1X)	OT9AKFVS	MT1X_HUMAN	Increases Expression	[18]
Complement factor H-related protein 3 (CFHR3)	OTYL8SDO	FHR3_HUMAN	Affects Expression	[18]
Nuclear factor 1 X-type (NFIX)	OT1DPZAE	NFIX_HUMAN	Decreases Expression	[18]
Phosphoenolpyruvate carboxykinase , mitochondrial (PCK2)	OTJ8LX4N	PCKGM_HUMAN	Decreases Expression	[18]
Organic solute transporter subunit alpha (SLC51A)	OTDJRZ0P	OSTA_HUMAN	Increases Expression	[18]
Organic solute transporter subunit beta (SLC51B)	OT4WYPSR	OSTB_HUMAN	Increases Expression	[18]
Liver-expressed antimicrobial peptide 2 (LEAP2)	OTUOPIS5	LEAP2_HUMAN	Affects Expression	[18]
N-acetylmuramoyl-L-alanine amidase (PGLYRP2)	OTF8319A	PGRP2_HUMAN	Affects Expression	[18]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Expression	[18]
Normal mucosa of esophagus-specific gene 1 protein (C15ORF48)	OT85J32K	NMES1_HUMAN	Affects Expression	[18]
ATP-binding cassette sub-family G member 5 (ABCG5)	OT1OMY93	ABCG5_HUMAN	Affects Expression	[18]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Decreases Expression	[18]
Solute carrier family 22 member 7 (SLC22A7)	OTKTNH1W	S22A7_HUMAN	Affects Expression	[18]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Expression	[22]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Decreases Expression	[22]
Coxsackievirus and adenovirus receptor (CXADR)	OT9ZP02A	CXAR_HUMAN	Decreases Expression	[23]

References

• [1] CheMBL Affinity Phenotypic Cellular Interaction Assay ID: CHEMBL1125966
• [2] Approved antiretroviral drugs. Antiretroviral Drugs. Company report of AVERT. 2009.
• [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: 3494).
• [4] Bosentan FDA Label
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [7] Induction of multiple drug transporters by efavirenz. J Pharmacol Sci. 2009 Feb;109(2):242-50.
• [8] Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital. J Clin Pharmacol. 2004 Nov;44(11):1273-81.
• [9] CYP2B6 genotype-dependent inhibition of CYP1A2 and induction of CYP2A6 by the antiretroviral drug efavirenz in healthy volunteers. Clin Transl Sci. 2019 Nov;12(6):657-666.
• [10] Evaluation of CYP2B6 induction and prediction of clinical drug-drug interactions: considerations from the IQ consortium induction working group-an industry perspective. Drug Metab Dispos. 2016 Oct;44(10):1720-30.
• [11] Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol. 2001 Jan;41(1):85-91.
• [12] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [13] Lon protease: a novel mitochondrial matrix protein in the interconnection between drug-induced mitochondrial dysfunction and endoplasmic reticulum stress. Br J Pharmacol. 2017 Dec;174(23):4409-4429. doi: 10.1111/bph.14045. Epub 2017 Nov 7.
• [14] Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes. Toxicol Appl Pharmacol. 2011 Dec 1;257(2):227-34. doi: 10.1016/j.taap.2011.09.008. Epub 2011 Sep 19.
• [15] Reverse transcriptase inhibitors down-regulate cell proliferation in vitro and in vivo and restore thyrotropin signaling and iodine uptake in human thyroid anaplastic carcinoma. J Clin Endocrinol Metab. 2005 Oct;90(10):5663-71. doi: 10.1210/jc.2005-0367. Epub 2005 Jul 19.
• [16] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [17] Effects of nevirapine and efavirenz on human adipocyte differentiation, gene expression, and release of adipokines and cytokines. Antiviral Res. 2011 Aug;91(2):112-9. doi: 10.1016/j.antiviral.2011.04.018. Epub 2011 May 17.
• [18] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [19] Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos. 2007 Aug;35(8):1400-7.
• [20] Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos. 2007 Aug;35(8):1400-7.
• [21] Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin. Clin Pharmacokinet. 2003;42(3):293-301.
• [22] From the Cover: MechanisticInsights in Cytotoxic and Cholestatic Potential of the Endothelial Receptor Antagonists Using HepaRG Cells. Toxicol Sci. 2017 Jun 1;157(2):451-464. doi: 10.1093/toxsci/kfx062.
• [23] Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells. J Gen Virol. 2010 Aug;91(Pt 8):1959-1970. doi: 10.1099/vir.0.020065-0. Epub 2010 Apr 14.