Details of the Drug Combination

General Information of Drug Combination (ID: DCLCKLS)

• Drug Combination Name: Pyrazinamide + Efavirenz
• Indication: Chronic myelogenous leukemia; Status: Investigative [1]
• Component Drugs:
  Pyrazinamide (DM4IF32): Small molecular drug
  Efavirenz (DMC0GSJ): Small molecular drug
• High-throughput Screening Result:
  Testing Cell Line: KBM-7
  Zero Interaction Potency (ZIP) Score: 28.97
  Bliss Independence Score: 28.97
  Loewe Additivity Score: 43.46
  LHighest Single Agent (HSA) Score: 43.46

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Pyrazinamide

Disease Entry	ICD 11	Status	REF
Meningeal tuberculosis	N.A.	Approved	[2]
Mycobacterium infection	1B10-1B21	Approved	[3]
Pulmonary tuberculosis	1B10.Z	Approved	[2]

Pyrazinamide Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Bacterial Fatty acid synthetase I (Bact inhA)	TTVTX4N	INHA_MYCTU	Inhibitor	[6]

Pyrazinamide Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[7]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[7]
Nicotinamidase (pncA)	DERQS6E	B0VA03_ACIBY	Metabolism	[8]

Pyrazinamide Interacts with 9 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Serine/threonine-protein kinase/endoribonuclease IRE1 (ERN1)	OTY9R6FZ	ERN1_HUMAN	Increases Expression	[5]
Eukaryotic translation initiation factor 2 subunit 1 (EIF2S1)	OTM0GDTP	IF2A_HUMAN	Increases Phosphorylation	[5]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Increases Expression	[5]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[5]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Expression	[5]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[5]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Cleavage	[5]
Solute carrier family 22 member 12 (SLC22A12)	OT72ZAWS	S22AC_HUMAN	Affects Activity	[9]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Phosphorylation	[5]

Indication(s) of Efavirenz

Disease Entry	ICD 11	Status	REF
Human immunodeficiency virus infection	1C62	Approved	[4]

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	[10]

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	[11]
Multidrug resistance-associated protein 3 (ABCC3)	DTQ3ZHF	MRP3_HUMAN	Substrate	[12]

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	[13]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Metabolism	[14]
Cytochrome P450 2B6 (CYP2B6)	DEPKLMQ	CP2B6_HUMAN	Metabolism	[15]

Efavirenz Interacts with 32 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Expression	[16]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[17]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[17]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[18]
Dynamin-1-like protein (DNM1L)	OTXK1Q1G	DNM1L_HUMAN	Affects Localization	[19]
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[20]
Dynamin-like 120 kDa protein, mitochondrial (OPA1)	OTJGNWPW	OPA1_HUMAN	Increases Expression	[19]
Mitofusin-2 (MFN2)	OTPYN8A3	MFN2_HUMAN	Increases Expression	[19]
Thyroglobulin (TG)	OT3ELHIJ	THYG_HUMAN	Increases Expression	[21]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[22]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Secretion	[23]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Secretion	[23]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Phosphorylation	[20]
Lipoprotein lipase (LPL)	OTTW0267	LIPL_HUMAN	Decreases Expression	[23]
Thyroid peroxidase (TPO)	OTJJLL20	PERT_HUMAN	Increases Expression	[21]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Secretion	[23]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Secretion	[23]
Hepatocyte growth factor (HGF)	OTGHUA23	HGF_HUMAN	Increases Secretion	[23]
Thyrotropin receptor (TSHR)	OT0BC8LB	TSHR_HUMAN	Increases Expression	[21]
Calnexin (CANX)	OTYP1F6J	CALX_HUMAN	Affects Localization	[19]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[19]
Lon protease homolog, mitochondrial (LONP1)	OT665WYT	LONM_HUMAN	Increases Expression	[19]
Sterol regulatory element-binding protein 1 (SREBF1)	OTWBRPAI	SRBP1_HUMAN	Decreases Expression	[23]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Expression	[23]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Expression	[23]
Mitogen-activated protein kinase 8 (MAPK8)	OTEREYS5	MK08_HUMAN	Increases Phosphorylation	[20]
CCAAT/enhancer-binding protein alpha (CEBPA)	OTOM9OE4	CEBPA_HUMAN	Decreases Expression	[23]
Adiponectin (ADIPOQ)	OTNX23LE	ADIPO_HUMAN	Decreases Expression	[23]
Regulator of microtubule dynamics protein 3 (RMDN3)	OTKO7AUM	RMD3_HUMAN	Increases Expression	[19]
Mitogen-activated protein kinase kinase kinase 5 (MAP3K5)	OTQR6ENW	M3K5_HUMAN	Increases Phosphorylation	[20]
Eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3)	OT0DZGY4	E2AK3_HUMAN	Increases Expression	[19]
Mitochondrial fission 1 protein (FIS1)	OT2HL10J	FIS1_HUMAN	Increases Expression	[19]

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] Pyrazinamide 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: 7287).
• [4] Approved antiretroviral drugs. Antiretroviral Drugs. Company report of AVERT. 2009.
• [5] Pyrazinamide-induced hepatotoxicity is alleviated by 4-PBA via inhibition of the PERK-eIF2-ATF4-CHOP pathway. Toxicology. 2017 Mar 1;378:65-75. doi: 10.1016/j.tox.2017.01.002. Epub 2017 Jan 4.
• [6] Pyrazinamide inhibits the eukaryotic-like fatty acid synthetase I (FASI) of Mycobacterium tuberculosis. Nat Med. 2000 Sep;6(9):1043-7.
• [7] The metabolism of pyrazoloacridine (NSC 366140) by cytochromes p450 and flavin monooxygenase in human liver microsomes. Clin Cancer Res. 2004 Feb 15;10(4):1471-80.
• [8] Specificity and mechanism of Acinetobacter baumanii nicotinamidase: implications for activation of the front-line tuberculosis drug pyrazinamide. Angew Chem Int Ed Engl. 2009;48(48):9176-9.
• [9] Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol. 2004 Jan;15(1):164-73. doi: 10.1097/01.asn.0000105320.04395.d0.
• [10] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [11] Human intestinal transporter database: QSAR modeling and virtual profiling of drug uptake, efflux and interactions. Pharm Res. 2013 Apr;30(4):996-1007.
• [12] Induction of multiple drug transporters by efavirenz. J Pharmacol Sci. 2009 Feb;109(2):242-50.
• [13] Induction of CYP3A4 by efavirenz in primary human hepatocytes: comparison with rifampin and phenobarbital. J Clin Pharmacol. 2004 Nov;44(11):1273-81.
• [14] 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.
• [15] 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.
• [16] Use of immortalized human hepatocytes to predict the magnitude of clinical drug-drug interactions caused by CYP3A4 induction. Drug Metab Dispos. 2006 Oct;34(10):1742-8.
• [17] Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol. 2001 Jan;41(1):85-91.
• [18] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [23] 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.