Details of the Drug Combination

General Information of Drug Combination (ID: DCZAJNU)

• Drug Combination Name: Voriconazole + Atazanavir
• Indication: Human Immunodeficiency Virus Type 1 (HIV-1); Status: Phase 1 [1]
• Component Drugs:
  Voriconazole (DMAOL2S): Small molecular drug
  Atazanavir (DMSYRBX): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Voriconazole

Disease Entry	ICD 11	Status	REF
Aspergillosis	1F20	Approved	[2]
Candidiasis	1F23	Approved	[2]
Fusariosis	N.A.	Approved	[2]
Invasive aspergillosis	1F20.0	Approved	[3]
Invasive candidiasis	1F23	Approved	[2]
Neuroaspergillosis	N.A.	Approved	[2]
Candidemia	1F23.3Y	Investigative	[2]
Esophageal candidiasis	N.A.	Investigative	[2]

Voriconazole 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	[5]

Voriconazole Interacts with 4 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[6]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[7]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Metabolism	[7]
Prostaglandin G/H synthase 1 (COX-1)	DE073H6	PGH1_HUMAN	Metabolism	[8]

Voriconazole Interacts with 7 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[9]
Cytochrome P450 2C9 (CYP2C9)	OTGLBN29	CP2C9_HUMAN	Decreases Activity	[9]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Activity	[9]
Carbonic anhydrase 1 (CA1)	OTNFBVVQ	CAH1_HUMAN	Decreases Activity	[10]
Carbonic anhydrase 2 (CA2)	OTJRMUAG	CAH2_HUMAN	Decreases Activity	[10]
Cytochrome P450 1B1 (CYP1B1)	OTYXFLSD	CP1B1_HUMAN	Decreases Activity	[11]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Response To Substance	[12]

Indication(s) of Atazanavir

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

Atazanavir Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Human immunodeficiency virus Protease (HIV PR)	TT5FNQT	POL_HV1B1	Modulator	[15]

Atazanavir Interacts with 5 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[16]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[17]
Cytochrome P450 3A5 (CYP3A5)	DEIBDNY	CP3A5_HUMAN	Metabolism	[16]
Cytochrome P450 3A7 (CYP3A7)	DERD86B	CP3A7_HUMAN	Metabolism	[16]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Metabolism	[18]

Atazanavir Interacts with 47 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Expression	[14]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[19]
ATP-binding cassette sub-family C member 3 (ABCC3)	OTC3IJV4	MRP3_HUMAN	Decreases Expression	[14]
Nuclear receptor subfamily 1 group I member 2 (NR1I2)	OTC5U0N5	NR1I2_HUMAN	Decreases Expression	[14]
Phosphatidylinositol 3-kinase C2 domain-containing subunit gamma (PIK3C2G)	OTW3LY1C	P3C2G_HUMAN	Decreases Expression	[14]
Aflatoxin B1 aldehyde reductase member 3 (AKR7A3)	OTW3GO4Y	ARK73_HUMAN	Decreases Expression	[14]
Ubiquitin-like modifier-activating enzyme ATG7 (ATG7)	OTVT4YA1	ATG7_HUMAN	Increases Expression	[14]
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Affects Binding	[20]
Catalase (CAT)	OTHEBX9R	CATA_HUMAN	Decreases Expression	[14]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[14]
Plasminogen activator inhibitor 1 (SERPINE1)	OTT0MPQ3	PAI1_HUMAN	Increases Expression	[14]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[21]
Epoxide hydrolase 1 (EPHX1)	OTBKWQER	HYEP_HUMAN	Decreases Expression	[14]
Glutathione S-transferase A1 (GSTA1)	OTA7K5XA	GSTA1_HUMAN	Decreases Expression	[14]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[21]
Macrophage colony-stimulating factor 1 (CSF1)	OT68M7RD	CSF1_HUMAN	Increases Expression	[14]
C-C motif chemokine 3 (CCL3)	OTW2H3ND	CCL3_HUMAN	Increases Expression	[22]
Endoplasmic reticulum chaperone BiP (HSPA5)	OTFUIRAO	BIP_HUMAN	Decreases Expression	[14]
C-C motif chemokine 2 (CCL2)	OTAD2HEL	CCL2_HUMAN	Increases Expression	[22]
Fos-related antigen 1 (FOSL1)	OT9YTYMB	FOSL1_HUMAN	Increases Expression	[14]
Glutathione peroxidase 2 (GPX2)	OTXI2NTI	GPX2_HUMAN	Decreases Expression	[14]
Cyclic AMP-dependent transcription factor ATF-4 (ATF4)	OTRFV19J	ATF4_HUMAN	Increases Expression	[14]
Cyclic AMP-dependent transcription factor ATF-6 alpha (ATF6)	OTAFHAVI	ATF6A_HUMAN	Increases Expression	[14]
Cytochrome P450 2B6 (CYP2B6)	OTOYO4S7	CP2B6_HUMAN	Decreases Expression	[14]
Cytochrome P450 7A1 (CYP7A1)	OT8Z5KLD	CP7A1_HUMAN	Decreases Expression	[14]
Phosphatidylinositol 3-kinase regulatory subunit alpha (PIK3R1)	OT5BZ1J9	P85A_HUMAN	Decreases Expression	[14]
DNA damage-inducible transcript 3 protein (DDIT3)	OTI8YKKE	DDIT3_HUMAN	Increases Expression	[14]
Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6)	OTK13JKC	MP2K6_HUMAN	Decreases Expression	[14]
Flavin-containing monooxygenase 1 (FMO1)	OTTHSQKP	FMO1_HUMAN	Decreases Expression	[14]
Sulfotransferase 2A1 (SULT2A1)	OT0ISKQ4	ST2A1_HUMAN	Decreases Expression	[14]
Peptidyl-prolyl cis-trans isomerase FKBP5 (FKBP5)	OT404F9K	FKBP5_HUMAN	Decreases Expression	[14]
Sequestosome-1 (SQSTM1)	OTGY5D5J	SQSTM_HUMAN	Increases Expression	[14]
Hepatic sodium/bile acid cotransporter (SLC10A1)	OTUJVMCL	NTCP_HUMAN	Decreases Expression	[14]
Nuclear receptor subfamily 1 group I member 3 (NR1I3)	OTS3SGH7	NR1I3_HUMAN	Decreases Expression	[14]
MAP kinase-activated protein kinase 3 (MAPKAPK3)	OT7IWJNI	MAPK3_HUMAN	Increases Expression	[14]
Glutathione S-transferase A3 (GSTA3)	OTJ3REE3	GSTA3_HUMAN	Decreases Expression	[14]
DnaJ homolog subfamily C member 10 (DNAJC10)	OTD2EG0R	DJC10_HUMAN	Increases Expression	[14]
Mixed lineage kinase domain-like protein (MLKL)	OTDSLC81	MLKL_HUMAN	Increases Expression	[14]
DnaJ homolog subfamily C member 9 (DNAJC9)	OTDBQBNZ	DNJC9_HUMAN	Increases Expression	[14]
ATP-binding cassette sub-family C member 2 (ABCC2)	OTJSIGV5	MRP2_HUMAN	Decreases Expression	[14]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Decreases Expression	[14]
Microtubule-associated proteins 1A/1B light chain 3B (MAP1LC3B)	OTUYHB84	MLP3B_HUMAN	Increases Expression	[14]
Ubiquitin carboxyl-terminal hydrolase CYLD (CYLD)	OT37FKH0	CYLD_HUMAN	Increases Expression	[14]
Transcription factor MafF (MAFF)	OT9B7MX0	MAFF_HUMAN	Increases Expression	[14]
Endophilin-B1 (SH3GLB1)	OTAZ5OP8	SHLB1_HUMAN	Increases Expression	[14]
Solute carrier organic anion transporter family member 1B1 (SLCO1B1)	OTNEN8QK	SO1B1_HUMAN	Decreases Expression	[14]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases Transport	[23]

References

• [1] ClinicalTrials.gov (NCT00833482) Drug Interactions Between Voriconazole and Atazanavir Coadministered as Atazanavir/Ritonavir in Healthy Participants
• [2] Voriconazole FDA Label
• [3] Disk diffusion test and E-test with enriched Mueller-Hinton agar for determining susceptibility of Candida species to voriconazole and fluconazole. J Microbiol Immunol Infect. 2009 Apr;42(2):148-53.
• [4] Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes. Biochem Pharmacol. 2007 Jun 15;73(12):2020-6.
• [7] Effect of voriconazole on the pharmacokinetics of diclofenac. Fundam Clin Pharmacol. 2007 Dec;21(6):651-6.
• [8] Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675.
• [9] 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.
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• [11] 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.
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• [13] Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016 Apr;99(4):363-9. doi: 10.1002/cpt.269. Epub 2015 Nov 9.
• [14] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
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• [16] Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos. 2005 Jun;33(6):764-70.
• [17] In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos. 2005 Nov;33(11):1729-39.
• [18] Atazanavir for the treatment of human immunodeficiency virus infection. Pharmacotherapy. 2004 Dec;24(12):1732-47.
• [19] Early identification of clinically relevant drug interactions with the human bile salt export pump (BSEP/ABCB11). Toxicol Sci. 2013 Dec;136(2):328-43.
• [20] Binding of anti-HIV drugs to human serum albumin. IUBMB Life. 2004 Oct;56(10):609-14. doi: 10.1080/15216540400016286.
• [21] Heme oxygenase-1-derived bilirubin counteracts HIV protease inhibitor-mediated endothelial cell dysfunction. Free Radic Biol Med. 2016 May;94:218-29. doi: 10.1016/j.freeradbiomed.2016.03.003. Epub 2016 Mar 8.
• [22] Some HIV antiretrovirals increase oxidative stress and alter chemokine, cytokine or adiponectin production in human adipocytes and macrophages. Antivir Ther. 2007;12(4):489-500.
• [23] Interactions of protease inhibitors atazanavir and ritonavir with ABCB1, ABCG2, and ABCC2 transporters: Effect on transplacental disposition in rats. Reprod Toxicol. 2018 Aug;79:57-65. doi: 10.1016/j.reprotox.2018.05.008. Epub 2018 May 30.