Details of the Drug Combination

General Information of Drug Combination (ID: DC4839V)

• Drug Combination Name: Bifonazole + Urea
• Indication: Foot Dermatoses; Status: Phase 4 [1]
• Component Drugs:
  Bifonazole (DM3KN7V): Small molecular drug
  Urea (DMUK75B): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Bifonazole

Disease Entry	ICD 11	Status	REF
Fungal infection	1F29-1F2F	Approved	[2]

Bifonazole 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	[5]

Bifonazole 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	[6]
Aromatase (CYP19A1)	OTZ6XF74	CP19A_HUMAN	Decreases Activity	[7]
Lanosterol 14-alpha demethylase (CYP51A1)	OTAYHG9C	CP51A_HUMAN	Decreases Activity	[8]

Indication(s) of Urea

Disease Entry	ICD 11	Status	REF
Dermatological disease	DA24.Y	Approved	[3]
Exanthem	N.A.	Approved	[4]
Impacted cerumen	AA42	Approved	[4]
Pityriasis simplex	N.A.	Approved	[4]
Skin disease	EA00-EM0Z	Approved	[4]
Tinea versicolor	1F2D.0	Approved	[4]

Urea Interacts with 1 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic anion transporting polypeptide 1A2 (SLCO1A2)	DTE2B1D	SO1A2_HUMAN	Substrate	[9]

Urea Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Albumin (ALB)	OTVMM513	ALBU_HUMAN	Decreases Folding	[10]
Alpha-fetoprotein (AFP)	OT9GG3ZI	FETA_HUMAN	Increases Expression	[11]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[12]
Fibroblast growth factor receptor 1 (FGFR1)	OT4GLCXW	FGFR1_HUMAN	Decreases Activity	[13]
Vascular endothelial growth factor receptor 2 (KDR)	OT15797V	VGFR2_HUMAN	Decreases Activity	[13]
Carnitine O-palmitoyltransferase 1, liver isoform (CPT1A)	OTI862QH	CPT1A_HUMAN	Increases Expression	[14]
Peroxisome proliferator-activated receptor alpha (PPARA)	OTK095PP	PPARA_HUMAN	Increases Activity	[14]
Aquaporin-10 (AQP10)	OT8Q5UWS	AQP10_HUMAN	Increases Uptake	[15]
Arginase-2, mitochondrial (ARG2)	OTCPI0E8	ARGI2_HUMAN	Increases Chemical Synthesis	[16]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Decreases Abundance	[17]
Aquaporin-9 (AQP9)	OTLGH5ZY	AQP9_HUMAN	Increases Transport	[18]
Parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R)	OTQF5ZAK	PTH1R_HUMAN	Increases ADR	[19]
Hemoglobin subunit alpha (HBA1)	OTW2BQF4	HBA_HUMAN	Increases ADR	[19]

References

• [1] ClinicalTrials.gov (NCT02705664) Treatment of Onychomycosis With Loceryl (Amorolfine) Nail Lacquer 5% Versus a Two-course Treatment With Urea 40% Ointment and Bifonazole Cream 1%
• [2] Drug information of Bifonazole, 2008. eduDrugs.
• [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: 4539).
• [4] Urea FDA Label
• [5] Investigation of the role of cytochrome P450 2B4 active site residues in substrate metabolism based on crystal structures of the ligand-bound enzyme. Arch Biochem Biophys. 2006 Nov 1;455(1):61-7.
• [6] Inhibition of cytochrome P450 enzymes participating in p-nitrophenol hydroxylation by drugs known as CYP2E1 inhibitors. Chem Biol Interact. 2004 Apr 15;147(3):331-40.
• [7] Comparative assessment of the inhibition of recombinant human CYP19 (aromatase) by azoles used in agriculture and as drugs for humans. Endocr Res. 2004 Aug;30(3):387-94.
• [8] Comparison of lanosterol-14 alpha-demethylase (CYP51) of human and Candida albicans for inhibition by different antifungal azoles. Toxicology. 2006 Nov 10;228(1):24-32. doi: 10.1016/j.tox.2006.08.007. Epub 2006 Aug 12.
• [9] Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. Exp Hematol. 2011 Apr;39(4):446-56.
• [10] Urea-induced denaturation of human serum albumin labeled with acrylodan. J Protein Chem. 2002 Feb;21(2):75-9. doi: 10.1023/a:1014508610017.
• [11] Carcinoembryonic antigen, alpha-fetoprotein, and prostate-specific antigen in the sera of industrial workers exposed to phenol, formaldehyde, urea, and mixed vapors. Inhal Toxicol. 2006 Dec;18(13):1041-6. doi: 10.1080/08958370600904603.
• [12] Urea and hypertonicity increase expression of heme oxygenase-1 in murine renal medullary cells. Am J Physiol Renal Physiol. 2001 Nov;281(5):F983-91. doi: 10.1152/ajprenal.0358.2000.
• [13] Synthesis and structure-activity relationships of soluble 7-substituted 3-(3,5-dimethoxyphenyl)-1,6-naphthyridin-2-amines and related ureas as dual inhibitors of the fibroblast growth factor receptor-1 and vascular endothelial growth factor receptor-2 tyrosine kinases. J Med Chem. 2005 Jul 14;48(14):4628-53. doi: 10.1021/jm0500931.
• [14] Activation of peroxisome proliferator-activated receptor alpha by substituted urea-derived soluble epoxide hydrolase inhibitors. J Pharmacol Exp Ther. 2005 Jul;314(1):260-70. doi: 10.1124/jpet.105.085605. Epub 2005 Mar 29.
• [15] Cloning and identification of a new member of water channel (AQP10) as an aquaglyceroporin. Biochim Biophys Acta. 2002 Jul 19;1576(3):335-40. doi: 10.1016/s0167-4781(02)00393-7.
• [16] Cells for bioartificial liver devices: the human hepatoma-derived cell line C3A produces urea but does not detoxify ammonia. Biotechnol Bioeng. 2008 Feb 15;99(3):644-51. doi: 10.1002/bit.21599.
• [17] Role of peroxynitrite and recombinant human manganese superoxide dismutase in reducing ischemia-reperfusion renal tissue injury. Transplant Proc. 2009 Nov;41(9):3603-10. doi: 10.1016/j.transproceed.2009.04.008.
• [18] Cloning and functional expression of a new aquaporin (AQP9) abundantly expressed in the peripheral leukocytes permeable to water and urea, but not to glycerol. Biochem Biophys Res Commun. 1998 Mar 6;244(1):268-74. doi: 10.1006/bbrc.1998.8252.
• [19] 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.