Tmic
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Record Information
Version2.0
Creation Date2009-07-30 17:58:59 UTC
Update Date2014-12-24 20:26:07 UTC
Accession NumberT3D3516
Identification
Common NameItraconazole
ClassSmall Molecule
DescriptionItraconazole is only found in individuals that have used or taken this drug. It is one of the triazole antifungal agents that inhibits cytochrome P-450-dependent enzymes resulting in impairment of ergosterol synthesis. It has been used against histoplasmosis, blastomycosis, cryptococcal meningitis & aspergillosis. [PubChem]Itraconazole interacts with 14-alpha demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Itraconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.
Compound Type
  • 14-alpha Demethylase Inhibitor
  • Amine
  • Antifungal Agent
  • Antiprotozoal Agent
  • Drug
  • Ether
  • Metabolite
  • Organic Compound
  • Organochloride
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
ITC
ITCZ
Itraconazol
Itraconazolum
Itrizole
ITZ
Onmel
Oriconazole
Sporal
Sporanox
Chemical FormulaC35H38Cl2N8O4
Average Molecular Mass705.633 g/mol
Monoisotopic Mass704.239 g/mol
CAS Registry Number84625-61-6
IUPAC Name1-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro-1H-1,2,4-triazol-5-one
Traditional Nameitraconazole
SMILES[H]C(C)(CC)N1N=CN(C1=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C(OC[C@@]2([H])CO[C@@](CN3C=NC=N3)(O2)C2=C(Cl)C=C(Cl)C=C2)C=C1
InChI IdentifierInChI=1S/C35H38Cl2N8O4/c1-3-25(2)45-34(46)44(24-40-45)29-7-5-27(6-8-29)41-14-16-42(17-15-41)28-9-11-30(12-10-28)47-19-31-20-48-35(49-31,21-43-23-38-22-39-43)32-13-4-26(36)18-33(32)37/h4-13,18,22-25,31H,3,14-17,19-21H2,1-2H3/t25?,31-,35-/m0/s1
InChI KeyInChIKey=VHVPQPYKVGDNFY-ZPGVKDDISA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as phenylpiperazines. Phenylpiperazines are compounds containing a phenylpiperazine skeleton, which consists of a piperazine bound to a phenyl group.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazinanes
Sub ClassPiperazines
Direct ParentPhenylpiperazines
Alternative Parents
Substituents
  • Phenylpiperazine
  • N-arylpiperazine
  • Phenyltriazole
  • Phenyl-1,2,4-triazole
  • Aminophenyl ether
  • Phenol ether
  • Phenoxy compound
  • Tertiary aliphatic/aromatic amine
  • 1,3-dichlorobenzene
  • Dialkylarylamine
  • Aniline or substituted anilines
  • Halobenzene
  • Alkyl aryl ether
  • Ketal
  • Chlorobenzene
  • Aryl halide
  • Benzenoid
  • Monocyclic benzene moiety
  • Aryl chloride
  • Azole
  • 1,2,4-triazole
  • Triazole
  • Meta-dioxolane
  • Heteroaromatic compound
  • Tertiary amine
  • Ether
  • Azacycle
  • Oxacycle
  • Acetal
  • Organochloride
  • Organohalogen compound
  • Organooxygen compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Organopnictogen compound
  • Amine
  • Organic oxygen compound
  • Organonitrogen compound
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological Roles
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point166.2°C
Boiling PointNot Available
SolubilityInsoluble
LogP5.66
Predicted Properties
PropertyValueSource
Water Solubility0.0096 g/LALOGPS
logP5.48ALOGPS
logP7.31ChemAxon
logS-4.9ALOGPS
pKa (Strongest Basic)3.92ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area100.79 ŲChemAxon
Rotatable Bond Count11ChemAxon
Refractivity200.4 m³·mol⁻¹ChemAxon
Polarizability74.7 ųChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash Key
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-00e9-6214197000-1ee5b13e7088e9cfe8f4View in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-0lz0-0594300000-f8fca354ab686af07f2dView in MoNA
LC-MS/MSLC-MS/MS Spectrum - LC-ESI-qTof , Positivesplash10-0lz0-0594300000-f8fca354ab686af07f2dView in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0udi-0329000000-18fc35342fd0b509b439View in MoNA
LC-MS/MSLC-MS/MS Spectrum - , positivesplash10-0a4i-0112100900-c45b863fbc00a8c449b4View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0a4i-2014019700-85126d2b5b6964cb167dView in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-03di-4911034000-399215ad81f2268c5d61View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00di-9132010000-ae7c2d5fe82a8f94b236View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-014i-9013020100-071002be4024d571dbb9View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-014i-9011000000-14b98a8a8e8671d57c64View in MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00or-7094010000-5df5528d83df0744427aView in MoNA
Toxicity Profile
Route of ExposureThe absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal.
Mechanism of ToxicityItraconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Itraconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.
MetabolismItraconazole is extensively metabolized by the liver into a large number of metabolites, including hydroxyitraconazole, the major metabolite. The main metabolic pathways are oxidative scission of the dioxolane ring, aliphatic oxidation at the 1-methylpropyl substituent, N-dealkylation of this 1-methylpropyl substituent, oxidative degradation of the piperazine ring and triazolone scission. Route of Elimination: Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4) in the liver, resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Half Life: 21 hours
Toxicity ValuesNo significant lethality was observed when itraconazole was administered orally to mice and rats at dosage levels of 320 mg/kg or to dogs at 200 mg/kg.
Lethal DoseNo significant lethality was observed when itraconazole was administered orally to mice and rats at dosage levels of 320 mg/kg or to dogs at 200 mg/kg. (1)
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsNot Available
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01167
HMDB IDHMDB15298
PubChem Compound ID55283
ChEMBL IDCHEMBL22587
ChemSpider ID49927
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID6076
BioCyc IDNot Available
CTD IDNot Available
Stitch IDItraconazole
PDB ID1YN
ACToR IDNot Available
Wikipedia LinkItraconazole
References
Synthesis Reference

Jong-Soo Woo, Hong-Gi Yi, “Antifungal oral composition containing itraconazole and process for preparing same.” U.S. Patent US6039981, issued May, 1998.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Drugs.com [Link]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Xenobiotic-transporting atpase activity
Specific Function:
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name:
ABCB1
Uniprot ID:
P08183
Molecular Weight:
141477.255 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.03 uMNot AvailableBindingDB 50127138
IC501.7 uMNot AvailableBindingDB 50127138
IC502.1 uMNot AvailableBindingDB 50127138
IC502.4 uMNot AvailableBindingDB 50127138
References
  1. Masuda S, Inui K: [Molecular mechanisms on drug transporters in the drug absorption and disposition]. Nihon Rinsho. 2002 Jan;60(1):65-73. [11808341 ]
  2. Lilja JJ, Backman JT, Laitila J, Luurila H, Neuvonen PJ: Itraconazole increases but grapefruit juice greatly decreases plasma concentrations of celiprolol. Clin Pharmacol Ther. 2003 Mar;73(3):192-8. [12621384 ]
  3. Sakaeda T, Iwaki K, Kakumoto M, Nishikawa M, Niwa T, Jin JS, Nakamura T, Nishiguchi K, Okamura N, Okumura K: Effect of micafungin on cytochrome P450 3A4 and multidrug resistance protein 1 activities, and its comparison with azole antifungal drugs. J Pharm Pharmacol. 2005 Jun;57(6):759-64. [15969931 ]
  4. Saito M, Hirata-Koizumi M, Miyake S, Hasegawa R: Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA and UK). Eur J Clin Pharmacol. 2005 Aug;61(7):531-6. Epub 2005 Jul 23. [16041596 ]
  5. Shon JH, Yoon YR, Hong WS, Nguyen PM, Lee SS, Choi YG, Cha IJ, Shin JG: Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism. Clin Pharmacol Ther. 2005 Aug;78(2):191-201. [16084853 ]
  6. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [12699389 ]
  7. Wang EJ, Lew K, Casciano CN, Clement RP, Johnson WW: Interaction of common azole antifungals with P glycoprotein. Antimicrob Agents Chemother. 2002 Jan;46(1):160-5. [11751127 ]
  8. Wang EJ, Casciano CN, Clement RP, Johnson WW: Active transport of fluorescent P-glycoprotein substrates: evaluation as markers and interaction with inhibitors. Biochem Biophys Res Commun. 2001 Nov 30;289(2):580-5. [11716514 ]
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide (PubMed:11159812). Catalyzes 4-beta-hydroxylation of cholesterol. May catalyze 25-hydroxylation of cholesterol in vitro (PubMed:21576599).
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.7 uMNot AvailableBindingDB 50127138
References
  1. Schwab D, Fischer H, Tabatabaei A, Poli S, Huwyler J: Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery. J Med Chem. 2003 Apr 24;46(9):1716-25. [12699389 ]
  2. Ohno T, Nakayama K, Nakade S, Kitagawa J, Ueda S, Miyabe H, Miyata Y, Ohnishi A: Effect of itraconazole on the pharmacokinetics of imidafenacin in healthy subjects. J Clin Pharmacol. 2008 Mar;48(3):330-4. doi: 10.1177/0091270007310386. Epub 2008 Jan 24. [18218784 ]
General Function:
Sterol 14-demethylase activity
Specific Function:
Catalyzes C14-demethylation of lanosterol; it transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol.
Gene Name:
CYP51A1
Uniprot ID:
Q16850
Molecular Weight:
56805.26 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC503.6 uMNot AvailableBindingDB 50127138
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
  2. Ekins S, Mankowski DC, Hoover DJ, Lawton MP, Treadway JL, Harwood HJ Jr: Three-dimensional quantitative structure-activity relationship analysis of human CYP51 inhibitors. Drug Metab Dispos. 2007 Mar;35(3):493-500. Epub 2006 Dec 28. [17194716 ]
General Function:
Chemokine receptor activity
Specific Function:
High affinity receptor for the C-C type chemokines CCL17/TARC, CCL22/MDC and CKLF isoform 1/CKLF1. The activity of this receptor is mediated by G(i) proteins which activate a phosphatidylinositol-calcium second messenger system. Can function as a chemoattractant homing receptor on circulating memory lymphocytes and as a coreceptor for some primary HIV-2 isolates. In the CNS, could mediate hippocampal-neuron survival.
Gene Name:
CCR4
Uniprot ID:
P51679
Molecular Weight:
41402.385 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.2 uMNot AvailableBindingDB 50127138
IC500.5 uMNot AvailableBindingDB 50127138
IC507.2 uMNot AvailableBindingDB 50127138
IC5011.4 uMNot AvailableBindingDB 50127138
References
  1. Sassano MF, Doak AK, Roth BL, Shoichet BK: Colloidal aggregation causes inhibition of G protein-coupled receptors. J Med Chem. 2013 Mar 28;56(6):2406-14. doi: 10.1021/jm301749y. Epub 2013 Mar 12. [23437772 ]
General Function:
Interleukin-8 receptor activity
Specific Function:
Receptor to interleukin-8, which is a powerful neutrophils chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This response is mediated via a G-protein that activate a phosphatidylinositol-calcium second messenger system. This receptor binds to IL-8 with a high affinity and to MGSA (GRO) with a low affinity.
Gene Name:
CXCR1
Uniprot ID:
P25024
Molecular Weight:
39790.735 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.1 uMNot AvailableBindingDB 50127138
IC505 uMNot AvailableBindingDB 50127138
IC5020.8 uMNot AvailableBindingDB 50127138
References
  1. Sassano MF, Doak AK, Roth BL, Shoichet BK: Colloidal aggregation causes inhibition of G protein-coupled receptors. J Med Chem. 2013 Mar 28;56(6):2406-14. doi: 10.1021/jm301749y. Epub 2013 Mar 12. [23437772 ]
General Function:
Vasopressin receptor activity
Specific Function:
Receptor for arginine vasopressin. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption.
Gene Name:
AVPR2
Uniprot ID:
P30518
Molecular Weight:
40278.57 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC500.8 uMNot AvailableBindingDB 50127138
IC506 uMNot AvailableBindingDB 50127138
IC5011.9 uMNot AvailableBindingDB 50127138
References
  1. Sassano MF, Doak AK, Roth BL, Shoichet BK: Colloidal aggregation causes inhibition of G protein-coupled receptors. J Med Chem. 2013 Mar 28;56(6):2406-14. doi: 10.1021/jm301749y. Epub 2013 Mar 12. [23437772 ]