Details of the Drug Combination

General Information of Drug Combination (ID: DC1V49W)

• Drug Combination Name: Isoniazid + Fluconazole
• Indication: Human Immunodeficiency Virus; Status: Phase 3 [1]
• Component Drugs:
  Isoniazid (DM5JVS3): Small molecular drug
  Fluconazole (DMOWZ6B): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Isoniazid

Disease Entry	ICD 11	Status	REF
Latent tuberculosis infection	N.A.	Approved	[2]
Pulmonary tuberculosis	1B10.Z	Approved	[2]
Tuberculosis	1B10-1B1Z	Approved	[3]

Isoniazid 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	[7]

Isoniazid Interacts with 3 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Metabolism	[8]
Catalase-peroxidase (katG)	DEAGY5M	KATG_SYNE7	Metabolism	[9]
Arylamine N-acetyltransferase (NAT)	DEXCQTM	A0A3P8LE58_TSUPA	Metabolism	[10]

Isoniazid Interacts with 59 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Alanine aminotransferase 1 (GPT)	OTOXOA0Q	ALAT1_HUMAN	Increases Expression	[11]
N-alpha-acetyltransferase 20 (NAA20)	OTJB0VA6	NAA20_HUMAN	Increases ADR	[12]
Cytochrome P450 2C8 (CYP2C8)	OTHCWT42	CP2C8_HUMAN	Decreases Activity	[13]
Nuclear protein 1 (NUPR1)	OT4FU8C0	NUPR1_HUMAN	Increases Expression	[14]
Inhibin beta E chain (INHBE)	OTOI2NYG	INHBE_HUMAN	Increases Expression	[14]
Protein DEPP1 (DEPP1)	OTB36PHJ	DEPP1_HUMAN	Increases Expression	[14]
Aldo-keto reductase family 1 member B10 (AKR1B10)	OTOA4HTH	AK1BA_HUMAN	Increases Expression	[6]
Tumor necrosis factor (TNF)	OT4IE164	TNFA_HUMAN	Increases Secretion	[6]
Interferon gamma (IFNG)	OTXG9JM7	IFNG_HUMAN	Increases Secretion	[6]
C-X-C motif chemokine 10 (CXCL10)	OTTLQ6S0	CXL10_HUMAN	Increases Secretion	[6]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Secretion	[6]
NAD(P)H dehydrogenase 1 (NQO1)	OTZGGIVK	NQO1_HUMAN	Increases Expression	[6]
Interleukin-10 (IL10)	OTIRFRXC	IL10_HUMAN	Increases Secretion	[6]
Interleukin-12 subunit alpha (IL12A)	OTDQT8GI	IL12A_HUMAN	Increases Secretion	[6]
Interleukin-12 subunit beta (IL12B)	OT0JF8A3	IL12B_HUMAN	Increases Secretion	[6]
Interleukin-17A (IL17A)	OTY72FT2	IL17_HUMAN	Increases Secretion	[6]
Sulfiredoxin-1 (SRXN1)	OTYDBO4L	SRXN1_HUMAN	Increases Expression	[6]
Gamma-butyrobetaine dioxygenase (BBOX1)	OTKEX4RK	BODG_HUMAN	Increases Expression	[15]
Alpha-fetoprotein (AFP)	OT9GG3ZI	FETA_HUMAN	Decreases Expression	[15]
Sodium/potassium-transporting ATPase subunit beta-1 (ATP1B1)	OTTO6ZP4	AT1B1_HUMAN	Increases Expression	[15]
Amyloid-beta precursor protein (APP)	OTKFD7R4	A4_HUMAN	Increases Expression	[15]
Osteopontin (SPP1)	OTJGC23Y	OSTP_HUMAN	Decreases Expression	[15]
Mucin-1 (MUC1)	OTHQI7IY	MUC1_HUMAN	Increases Expression	[15]
14-3-3 protein sigma (SFN)	OTLJCZ1U	1433S_HUMAN	Decreases Expression	[15]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Decreases Expression	[15]
Glutamate--cysteine ligase regulatory subunit (GCLM)	OT6CP234	GSH0_HUMAN	Decreases Expression	[15]
Claudin-2 (CLDN2)	OTRF3D6Y	CLD2_HUMAN	Increases Expression	[15]
Large neutral amino acids transporter small subunit 1 (SLC7A5)	OT2WPVXD	LAT1_HUMAN	Decreases Expression	[15]
Tribbles homolog 3 (TRIB3)	OTG5OS7X	TRIB3_HUMAN	Increases Expression	[15]
Procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2)	OTKOZRZP	PLOD2_HUMAN	Increases Expression	[16]
Transmembrane protease serine 2 (TMPRSS2)	OTN44YQ5	TMPS2_HUMAN	Affects Expression	[17]
Interleukin-1 alpha (IL1A)	OTPSGILV	IL1A_HUMAN	Increases Expression	[18]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Increases Expression	[18]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[19]
Antileukoproteinase (SLPI)	OTUNFUU8	SLPI_HUMAN	Increases Expression	[18]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Activity	[20]
Apoptosis regulator Bcl-2 (BCL2)	OT9DVHC0	BCL2_HUMAN	Decreases Expression	[20]
Glucose-6-phosphate 1-dehydrogenase (G6PD)	OT300SMK	G6PD_HUMAN	Decreases Activity	[20]
5-aminolevulinate synthase, non-specific, mitochondrial (ALAS1)	OTQY6ZSF	HEM1_HUMAN	Increases Expression	[21]
Ferrochelatase, mitochondrial (FECH)	OTDWEI6C	HEMH_HUMAN	Decreases Expression	[21]
Mitogen-activated protein kinase 3 (MAPK3)	OTCYKGKO	MK03_HUMAN	Decreases Phosphorylation	[11]
Mitogen-activated protein kinase 1 (MAPK1)	OTH85PI5	MK01_HUMAN	Decreases Phosphorylation	[11]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Increases Expression	[18]
Peroxisome proliferator-activated receptor gamma (PPARG)	OTHMARHO	PPARG_HUMAN	Decreases Expression	[22]
Caspase-3 (CASP3)	OTIJRBE7	CASP3_HUMAN	Increases Activity	[20]
Caspase-9 (CASP9)	OTD4RFFG	CASP9_HUMAN	Increases Activity	[20]
Apoptosis regulator BAX (BAX)	OTAW0V4V	BAX_HUMAN	Increases Expression	[11]
Interleukin-24 (IL24)	OT4VUWH1	IL24_HUMAN	Increases Expression	[18]
Nuclear respiratory factor 1 (NRF1)	OTOXWNV8	NRF1_HUMAN	Decreases Expression	[23]
Natural cytotoxicity triggering receptor 3 ligand 1 (NCR3LG1)	OT15YWU7	NR3L1_HUMAN	Increases Expression	[24]
PTB-containing, cubilin and LRP1-interacting protein (PID1)	OT5YJ7FI	PCLI1_HUMAN	Increases Expression	[18]
NAD-dependent protein deacetylase sirtuin-1 (SIRT1)	OTAYZMOY	SIR1_HUMAN	Decreases Expression	[23]
Angiotensin-converting enzyme 2 (ACE2)	OTTRZGU7	ACE2_HUMAN	Decreases Expression	[17]
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A)	OTHCDQ22	PRGC1_HUMAN	Decreases Expression	[23]
Arylamine N-acetyltransferase 2 (NAT2)	OTBPDQOY	ARY2_HUMAN	Decreases Acetylation	[25]
Eosinophil peroxidase (EPX)	OTFNDFOK	PERE_HUMAN	Increases Oxidation	[26]
Myeloperoxidase (MPO)	OTOOXLIN	PERM_HUMAN	Increases Oxidation	[27]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Increases Response To Substance	[28]
Glutathione S-transferase Mu 1 (GSTM1)	OTSBF2MO	GSTM1_HUMAN	Decreases Response To Substance	[29]

Indication(s) of Fluconazole

Disease Entry	ICD 11	Status	REF
Cryptococcal meningitis	N.A.	Approved	[4]
Fungal infection	1F29-1F2F	Approved	[5]
Invasive candidiasis	1F23	Approved	[4]
Mycoses	1F2Z	Approved	[4]
Oral candidiasis	1F23.0	Approved	[4]
Autoimmune polyendocrine syndrome type 1	N.A.	Investigative	[4]
Candidemia	1F23.3Y	Investigative	[4]
Esophageal candidiasis	N.A.	Investigative	[4]

Fluconazole Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Candida Cytochrome P450 51 (Candi ERG11)	TTTSOUD	CP51_CANAL	Modulator	[30]

Fluconazole Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[31]

Fluconazole Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[32]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[33]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Affects Activity	[34]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[34]
Steroidogenic acute regulatory protein, mitochondrial (STAR)	OTFEZ5AI	STAR_HUMAN	Increases Expression	[35]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Response To Substance	[36]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases ADR	[12]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Metabolism	[37]

References

• [1] ClinicalTrials.gov (NCT01825031) Reduction of EArly mortaLITY in HIV-infected Adults and Children Starting Antiretroviral Therapy
• [2] Isoniazid FDA Label
• [3] Novel agents in the management of Mycobacterium tuberculosis disease. Curr Med Chem. 2007;14(18):2000-8.
• [4] Fluconazole FDA Label
• [5] Fluconazole use as an important risk factor in the emergence of fluconazole-resistant Candida glabrata fungemia. Arch Intern Med. 2009 Aug 10;169(15):1444-5; author reply 1445.
• [6] Characterization of drug-specific signaling between primary human hepatocytes and immune cells. Toxicol Sci. 2017 Jul 1;158(1):76-89.
• [7] Diversity in enoyl-acyl carrier protein reductases. Cell Mol Life Sci. 2009 May;66(9):1507-17.
• [8] Inhibition of CYP2E1 catalytic activity in vitro by S-adenosyl-L-methionine. Biochem Pharmacol. 2005 Apr 1;69(7):1081-93.
• [9] Crystal structure of the catalase-peroxidase KatG W78F mutant from Synechococcus elongatus PCC7942 in complex with the antitubercular pro-drug isoniazid. FEBS Lett. 2015 Jan 2;589(1):131-7.
• [10] The actinobacterium Tsukamurella paurometabola has a functionally divergent arylamine N-acetyltransferase (NAT) homolog. World J Microbiol Biotechnol. 2019 Oct 31;35(11):174.
• [11] Quercetin protected against isoniazide-induced HepG2 cell apoptosis by activating the SIRT1/ERK pathway. J Biochem Mol Toxicol. 2019 Sep;33(9):e22369. doi: 10.1002/jbt.22369. Epub 2019 Jul 23.
• [12] 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.
• [13] Mechanism-based inactivation of human cytochrome P4502C8 by drugs in vitro. J Pharmacol Exp Ther. 2004 Dec;311(3):996-1007.
• [14] Determination of phospholipidosis potential based on gene expression analysis in HepG2 cells. Toxicol Sci. 2007 Mar;96(1):101-14.
• [15] Comparison of base-line and chemical-induced transcriptomic responses in HepaRG and RPTEC/TERT1 cells using TempO-Seq. Arch Toxicol. 2018 Aug;92(8):2517-2531.
• [16] Identification of differentially expressed genes in hepatic HepG2 cells treated with acetaminophen using suppression subtractive hybridization. Biol Pharm Bull. 2005 Jul;28(7):1148-53. doi: 10.1248/bpb.28.1148.
• [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.
• [18] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [19] Auto-oxidation of Isoniazid Leads to Isonicotinic-Lysine Adducts on Human Serum Albumin. Chem Res Toxicol. 2015 Jan 20;28(1):51-8. doi: 10.1021/tx500285k. Epub 2014 Dec 9.
• [20] Isoniazid-induced apoptosis in HepG2 cells: generation of oxidative stress and Bcl-2 down-regulation. Toxicol Mech Methods. 2010 Jun;20(5):242-51. doi: 10.3109/15376511003793325.
• [21] The Isoniazid Metabolites Hydrazine and Pyridoxal Isonicotinoyl Hydrazone Modulate Heme Biosynthesis. Toxicol Sci. 2019 Mar 1;168(1):209-224. doi: 10.1093/toxsci/kfy294.
• [22] Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes. Toxicol Appl Pharmacol. 2013 Dec 15;273(3):435-41. doi: 10.1016/j.taap.2013.10.005. Epub 2013 Oct 12.
• [23] AMPK activator acadesine fails to alleviate isoniazid-caused mitochondrial instability in HepG2 cells. J Appl Toxicol. 2017 Oct;37(10):1219-1224. doi: 10.1002/jat.3483. Epub 2017 May 29.
• [24] Enhanced activation of human NK cells by drug-exposed hepatocytes. Arch Toxicol. 2020 Feb;94(2):439-448. doi: 10.1007/s00204-020-02668-8. Epub 2020 Feb 14.
• [25] Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients. J Toxicol Sci. 2008 May;33(2):187-95. doi: 10.2131/jts.33.187.
• [26] Eosinophil peroxidase oxidizes isoniazid to form the active metabolite against M. tuberculosis, isoniazid-NAD(). Chem Biol Interact. 2019 May 25;305:48-53. doi: 10.1016/j.cbi.2019.03.019. Epub 2019 Mar 25.
• [27] Metabolism of isoniazid by neutrophil myeloperoxidase leads to isoniazid-NAD(+) adduct formation: A comparison of the reactivity of isoniazid with its known human metabolites. Biochem Pharmacol. 2016 Apr 15;106:46-55. doi: 10.1016/j.bcp.2016.02.003. Epub 2016 Feb 9.
• [28] Development of a highly sensitive cytotoxicity assay system for CYP3A4-mediated metabolic activation. Drug Metab Dispos. 2011 Aug;39(8):1388-95. doi: 10.1124/dmd.110.037077. Epub 2011 May 3.
• [29] Customised in vitro model to detect human metabolism-dependent idiosyncratic drug-induced liver injury. Arch Toxicol. 2018 Jan;92(1):383-399. doi: 10.1007/s00204-017-2036-4. Epub 2017 Jul 31.
• [30] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [31] Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol. 2000 Jun;56(3):225-9.
• [32] The novel azole R126638 is a selective inhibitor of ergosterol synthesis in Candida albicans, Trichophyton spp., and Microsporum canis. Antimicrob Agents Chemother. 2004 Sep;48(9):3272-8.
• [33] CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions. J Pharmacol Exp Ther. 2005 Jul;314(1):180-90.
• [34] The classic azole antifungal drugs are highly potent endocrine disruptors in vitro inhibiting steroidogenic CYP enzymes at concentrations lower than therapeutic Cmax. Toxicology. 2019 Sep 1;425:152247. doi: 10.1016/j.tox.2019.152247. Epub 2019 Jul 19.
• [35] Fluconazole inhibits human adrenocortical steroidogenesis in vitro. J Endocrinol. 2012 Dec;215(3):403-12. doi: 10.1530/JOE-12-0310. Epub 2012 Oct 4.
• [36] Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homolo... Antimicrob Agents Chemother. 2008 Oct;52(10):3597-603.
• [37] [Simultaneous determination of the inhibitory potency of compounds on the activity of five cytochrome P-450 enzymes using a cocktail probe substrates method]. Yao Xue Xue Bao. 2007 Jun;42(6):589-94.