Details of the Drug Combination

General Information of Drug Combination (ID: DC3TZ23)

• Drug Combination Name: Fluconazole + Posaconazole
• Indication: Candidiasis; Status: Phase 1 [1]
• Component Drugs:
  Fluconazole (DMOWZ6B): Small molecular drug
  Posaconazole (DMUL5EW): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Fluconazole

Disease Entry	ICD 11	Status	REF
Cryptococcal meningitis	N.A.	Approved	[2]
Fungal infection	1F29-1F2F	Approved	[3]
Invasive candidiasis	1F23	Approved	[2]
Mycoses	1F2Z	Approved	[2]
Oral candidiasis	1F23.0	Approved	[2]
Autoimmune polyendocrine syndrome type 1	N.A.	Investigative	[2]
Candidemia	1F23.3Y	Investigative	[2]
Esophageal candidiasis	N.A.	Investigative	[2]

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	[7]

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	[8]

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	[9]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[10]
Steroid 17-alpha-hydroxylase/17,20 lyase (CYP17A1)	OTZKVLVJ	CP17A_HUMAN	Affects Activity	[11]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[11]
Steroidogenic acute regulatory protein, mitochondrial (STAR)	OTFEZ5AI	STAR_HUMAN	Increases Expression	[12]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Response To Substance	[13]
ATP-dependent translocase ABCB1 (ABCB1)	OTEJROBO	MDR1_HUMAN	Increases ADR	[6]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Increases Metabolism	[14]

Indication(s) of Posaconazole

Disease Entry	ICD 11	Status	REF
Aspergillosis	1F20	Approved	[4]
Candidiasis	1F23	Approved	[5]
Chromomycosis	N.A.	Approved	[5]
Coccidioidomycosis	1F25	Approved	[5]
Fusariosis	N.A.	Approved	[5]

Posaconazole 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	Inhibitor	[15]

Posaconazole Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
P-glycoprotein 1 (ABCB1)	DTUGYRD	MDR1_HUMAN	Substrate	[16]

Posaconazole Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Metabolism	[17]
UDP-glucuronosyltransferase 1A1 (UGT1A1)	DEYGVN4	UD11_HUMAN	Metabolism	[18]

Posaconazole Interacts with 3 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Decreases Activity	[19]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[20]
11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2)	OTHF4H9U	DHI2_HUMAN	Decreases Activity	[21]

References

• [1] ClinicalTrials.gov (NCT03828773) PTX3-targeted Antifungal Prophylaxis
• [2] Fluconazole FDA Label
• [3] 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.
• [4] FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 022003.
• [5] Posaconazole FDA Label
• [6] 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.
• [7] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [8] Effect of fluconazole on plasma fluvastatin and pravastatin concentrations. Eur J Clin Pharmacol. 2000 Jun;56(3):225-9.
• [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.
• [10] CYP3A4 substrate selection and substitution in the prediction of potential drug-drug interactions. J Pharmacol Exp Ther. 2005 Jul;314(1):180-90.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] [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.
• [15] A new, broad-spectrum azole antifungal: posaconazole--mechanisms of action and resistance, spectrum of activity. Mycoses. 2006;49 Suppl 1:2-6.
• [16] KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361. (dg:DG01665)
• [17] Survey of computed tomography doses and establishment of national diagnostic reference levels in the Republic of Belarus. Radiat Prot Dosimetry. 2010 Apr-May;139(1-3):367-70.
• [18] Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of posaconazole (Noxafil). Drug Metab Dispos. 2004 Feb;32(2):267-71.
• [19] Posaconazole-increased vincristine neurotoxicity in a child: a case report. J Pediatr Hematol Oncol. 2009 Apr;31(4):292-5. doi: 10.1097/MPH.0b013e31819b9d01.
• [20] A multifactorial approach to hepatobiliary transporter assessment enables improved therapeutic compound development. Toxicol Sci. 2013 Nov;136(1):216-41.
• [21] Inhibition of 11-hydroxysteroid dehydrogenase 2 by the fungicides itraconazole and posaconazole. Biochem Pharmacol. 2017 Apr 15;130:93-103. doi: 10.1016/j.bcp.2017.01.010. Epub 2017 Jan 25.