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Identification
NameItraconazole
Accession NumberDB01167  (APRD00040)
TypeSmall Molecule
GroupsApproved, Investigational
Description

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]

Structure
Thumb
Synonyms
Itraconazol
Itraconazole
Itraconazolum
Itrizole (tn)
Oriconazole
Sporanox (tn)
External Identifiers
  • R51211
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Itraconazolecapsule100 mg/1oralCarilion Materials Management2005-02-01Not applicableUs
Itraconazolecapsule100 mg/1oralPatriot Pharmaceuticals2005-02-01Not applicableUs
Onmeltablet200 mg/1oralMerz Pharmaceuticals, LLC2012-11-01Not applicableUs
Sporanoxcapsule100 mgoralJanssen Inc1993-12-31Not applicableCanada
Sporanoxcapsule100 mg/1oralbryant ranch prepack1992-09-11Not applicableUs
Sporanoxsolution10 mg/mLoralJanssen Pharmaceuticals, Inc.1997-02-21Not applicableUs
Sporanoxcapsule100 mg/1oralJanssen Pharmaceuticals, Inc.1992-09-11Not applicableUs
Sporanox Oral Solution 10mg/mlsolution10 mgoralJanssen Inc1997-07-28Not applicableCanada
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Itraconazolecapsule100 mg/1oralEon Labs, Inc.2004-05-28Not applicableUs
Itraconazolecapsule100 mg/1oralMylan Pharmaceuticals Inc.2012-07-20Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
ItrizoleNot Available
OriconazoleNot Available
SporalNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNII304NUG5GF4
CAS number84625-61-6
WeightAverage: 705.633
Monoisotopic: 704.239307158
Chemical FormulaC35H38Cl2N8O4
InChI KeyInChIKey=VHVPQPYKVGDNFY-ZPGVKDDISA-N
InChI
InChI=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
IUPAC Name
1-(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
SMILES
CCC(C)N1N=CN(C1=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C(OC[[email protected]]2CO[C@@](CN3C=NC=N3)(O2)C2=C(Cl)C=C(Cl)C=C2)C=C1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as phenylpiperazines. These 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
  • N-arylpiperazine
  • Phenylpiperazine
  • Phenyl-1,3,4-triazole
  • Phenyl-1,2,4-triazole
  • Phenyltriazole
  • Substituted aniline
  • Dialkylarylamine
  • Phenol ether
  • 1,3-dichlorobenzene
  • Glycerol ether
  • Halobenzene
  • Chlorobenzene
  • Aniline
  • Alkyl aryl ether
  • Benzenoid
  • Monocyclic benzene moiety
  • Aryl halide
  • Aryl chloride
  • Heteroaromatic compound
  • 1,2,4-triazole
  • Triazole
  • Azole
  • Meta-dioxolane
  • Tertiary amine
  • Oxacycle
  • Azacycle
  • Ether
  • Acetal
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Organochloride
  • Organohalogen compound
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.
PharmacodynamicsItraconazole is an imidazole/triazole type antifungal agent. Itraconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 α-demethylation via the inhibition of the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell wall synthesis. The subsequent loss of normal sterols correlates with the accumulation of 14 α-methyl sterols in fungi and may be partly responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Itraconazole exhibits in vitro activity against Cryptococcus neoformans and Candida spp. Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans.
Mechanism of actionItraconazole 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.
Related Articles
AbsorptionThe absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal.
Volume of distribution
  • 796 ± 185 L
Protein binding99.8%
Metabolism

Itraconazole 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.

SubstrateEnzymesProduct
Itraconazole
hydroxyitraconazoleDetails
Route of eliminationItraconazole 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 life21 hours
Clearance
  • 381 +/- 95 mL/minute [IV administration]
ToxicityNo 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.
Affected organisms
  • Fungi, yeast and protozoans
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9973
Blood Brain Barrier-0.6151
Caco-2 permeable+0.5511
P-glycoprotein substrateSubstrate0.6397
P-glycoprotein inhibitor IInhibitor0.7973
P-glycoprotein inhibitor IINon-inhibitor0.88
Renal organic cation transporterNon-inhibitor0.7497
CYP450 2C9 substrateNon-substrate0.8116
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7408
CYP450 1A2 substrateNon-inhibitor0.7666
CYP450 2C9 inhibitorInhibitor0.618
CYP450 2D6 inhibitorNon-inhibitor0.8622
CYP450 2C19 inhibitorInhibitor0.5703
CYP450 3A4 inhibitorInhibitor0.5279
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.8219
Ames testAMES toxic0.5303
CarcinogenicityNon-carcinogens0.7478
BiodegradationNot ready biodegradable1.0
Rat acute toxicity3.3118 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.5782
hERG inhibition (predictor II)Inhibitor0.6096
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Capsuleoral100 mg/1
Tabletoral200 mg/1
Capsuleoral100 mg
Solutionoral10 mg/mL
Solutionoral10 mg
Prices
Unit descriptionCostUnit
Itraconazole 28 100 mg capsule Disp Pack270.89USD disp
Itraconazole powder32.13USD g
Sporanox 100 mg capsule12.14USD capsule
Itraconazole 100 mg capsule9.46USD capsule
Sporanox 10 mg/ml Solution1.41USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
CA1336498 No1995-08-012012-08-01Canada
CA2142848 No1999-11-162013-08-27Canada
US5633015 No1994-05-272014-05-27Us
US6407079 No1999-06-182019-06-18Us
US6509038 No1997-05-122017-05-12Us
US7081255 No1997-05-122017-05-12Us
US8486456 No2008-10-032028-10-03Us
US8591948 No1997-05-122017-05-12Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point166.2 °CNot Available
water solubilityInsolubleNot Available
logP5.66HTTP://WWW.RXLIST.COM
pKa3.70Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00964 mg/mLALOGPS
logP5.48ALOGPS
logP7.31ChemAxon
logS-4.9ALOGPS
pKa (Strongest Basic)3.92ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count9ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area100.79 Å2ChemAxon
Rotatable Bond Count11ChemAxon
Refractivity200.4 m3·mol-1ChemAxon
Polarizability74.7 Å3ChemAxon
Number of Rings7ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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.

US6039981
General ReferencesNot Available
External Links
ATC CodesJ02AC02
AHFS Codes
  • 08:14.08
PDB Entries
FDA labelDownload (1.58 MB)
MSDSDownload (73.6 KB)
Interactions
Drug Interactions
Drug
AcenocoumarolThe serum concentration of Acenocoumarol can be increased when it is combined with Itraconazole.
AfatinibThe serum concentration of Afatinib can be increased when it is combined with Itraconazole.
AlfuzosinThe serum concentration of Alfuzosin can be increased when it is combined with Itraconazole.
AliskirenThe serum concentration of Aliskiren can be increased when it is combined with Itraconazole.
AlmotriptanThe serum concentration of Almotriptan can be increased when it is combined with Itraconazole.
AlosetronThe serum concentration of Alosetron can be increased when it is combined with Itraconazole.
AlprazolamThe serum concentration of Alprazolam can be increased when it is combined with Itraconazole.
Aluminum hydroxideThe serum concentration of Itraconazole can be decreased when it is combined with Aluminum hydroxide.
AmlodipineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Amlodipine.
Amphotericin BThe therapeutic efficacy of Amphotericin B can be decreased when used in combination with Itraconazole.
AmrinoneThe risk or severity of adverse effects can be increased when Itraconazole is combined with Amrinone.
ApixabanThe serum concentration of Apixaban can be increased when it is combined with Itraconazole.
AripiprazoleThe serum concentration of Aripiprazole can be increased when it is combined with Itraconazole.
AstemizoleThe serum concentration of Astemizole can be increased when it is combined with Itraconazole.
AtorvastatinThe serum concentration of Atorvastatin can be increased when it is combined with Itraconazole.
AvanafilThe serum concentration of Avanafil can be increased when it is combined with Itraconazole.
AxitinibThe serum concentration of Axitinib can be increased when it is combined with Itraconazole.
BarnidipineThe serum concentration of Barnidipine can be increased when it is combined with Itraconazole.
BedaquilineThe serum concentration of Bedaquiline can be increased when it is combined with Itraconazole.
BepridilThe risk or severity of adverse effects can be increased when Itraconazole is combined with Bepridil.
BexaroteneThe serum concentration of Itraconazole can be decreased when it is combined with Bexarotene.
BoceprevirThe serum concentration of Boceprevir can be increased when it is combined with Itraconazole.
BortezomibThe serum concentration of Bortezomib can be increased when it is combined with Itraconazole.
BosentanThe serum concentration of Itraconazole can be decreased when it is combined with Bosentan.
BosutinibThe serum concentration of Bosutinib can be increased when it is combined with Itraconazole.
Brentuximab vedotinThe serum concentration of Brentuximab vedotin can be increased when it is combined with Itraconazole.
BrexpiprazoleThe serum concentration of Brexpiprazole can be increased when it is combined with Itraconazole.
BrinzolamideThe serum concentration of Brinzolamide can be increased when it is combined with Itraconazole.
BudesonideThe serum concentration of Budesonide can be increased when it is combined with Itraconazole.
BuspironeThe metabolism of Buspirone can be decreased when combined with Itraconazole.
BusulfanThe serum concentration of Busulfan can be increased when it is combined with Itraconazole.
CabazitaxelThe serum concentration of Cabazitaxel can be increased when it is combined with Itraconazole.
CabozantinibThe serum concentration of Cabozantinib can be increased when it is combined with Itraconazole.
Calcium carbonateThe serum concentration of Itraconazole can be decreased when it is combined with Calcium carbonate.
CarbamazepineThe serum concentration of Itraconazole can be decreased when it is combined with Carbamazepine.
CeritinibThe serum concentration of Ceritinib can be increased when it is combined with Itraconazole.
CilostazolThe serum concentration of Cilostazol can be increased when it is combined with Itraconazole.
CimetidineThe serum concentration of Itraconazole can be decreased when it is combined with Cimetidine.
CisaprideThe serum concentration of Cisapride can be increased when it is combined with Itraconazole.
CitalopramItraconazole may increase the QTc-prolonging activities of Citalopram.
CobicistatThe serum concentration of Cobicistat can be increased when it is combined with Itraconazole.
ColchicineThe serum concentration of Colchicine can be increased when it is combined with Itraconazole.
ConivaptanThe metabolism of Conivaptan can be decreased when combined with Itraconazole.
CrizotinibThe serum concentration of Crizotinib can be increased when it is combined with Itraconazole.
CyclosporineThe metabolism of Cyclosporine can be decreased when combined with Itraconazole.
Dabigatran etexilateThe serum concentration of the active metabolites of Dabigatran etexilate can be increased when Dabigatran etexilate is used in combination with Itraconazole.
DabrafenibThe serum concentration of Itraconazole can be decreased when it is combined with Dabrafenib.
DaclatasvirThe serum concentration of Daclatasvir can be increased when it is combined with Itraconazole.
DapoxetineThe serum concentration of Dapoxetine can be increased when it is combined with Itraconazole.
DarunavirThe serum concentration of Itraconazole can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Dasatinib can be increased when it is combined with Itraconazole.
DeferasiroxThe serum concentration of Itraconazole can be decreased when it is combined with Deferasirox.
DicoumarolThe serum concentration of Dicoumarol can be increased when it is combined with Itraconazole.
DidanosineDidanosine can cause a decrease in the absorption of Itraconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
DienogestThe serum concentration of Dienogest can be increased when it is combined with Itraconazole.
DigoxinThe serum concentration of Digoxin can be increased when it is combined with Itraconazole.
DihydroergotamineThe serum concentration of Dihydroergotamine can be increased when it is combined with Itraconazole.
DisopyramideThe serum concentration of Disopyramide can be increased when it is combined with Itraconazole.
DocetaxelThe metabolism of Docetaxel can be decreased when combined with Itraconazole.
DofetilideThe metabolism of Dofetilide can be decreased when combined with Itraconazole.
DomperidoneThe serum concentration of Domperidone can be increased when it is combined with Itraconazole.
DoxorubicinThe serum concentration of Doxorubicin can be increased when it is combined with Itraconazole.
DronabinolThe serum concentration of Dronabinol can be increased when it is combined with Itraconazole.
DronedaroneThe serum concentration of Dronedarone can be increased when it is combined with Itraconazole.
DrospirenoneThe serum concentration of Drospirenone can be increased when it is combined with Itraconazole.
DutasterideThe serum concentration of Dutasteride can be increased when it is combined with Itraconazole.
EdoxabanThe serum concentration of Edoxaban can be increased when it is combined with Itraconazole.
EfavirenzThe serum concentration of Itraconazole can be decreased when it is combined with Efavirenz.
EletriptanThe serum concentration of Eletriptan can be increased when it is combined with Itraconazole.
EliglustatThe serum concentration of Eliglustat can be increased when it is combined with Itraconazole.
ElvitegravirThe serum concentration of Elvitegravir can be increased when it is combined with Itraconazole.
EnzalutamideThe serum concentration of Itraconazole can be decreased when it is combined with Enzalutamide.
EplerenoneThe serum concentration of Eplerenone can be increased when it is combined with Itraconazole.
Ergoloid mesylateThe serum concentration of Ergoloid mesylate can be increased when it is combined with Itraconazole.
ErgonovineThe serum concentration of Ergonovine can be increased when it is combined with Itraconazole.
ErgotamineThe serum concentration of Ergotamine can be increased when it is combined with Itraconazole.
ErlotinibThe serum concentration of Erlotinib can be increased when it is combined with Itraconazole.
EsomeprazoleThe serum concentration of Itraconazole can be decreased when it is combined with Esomeprazole.
EstazolamThe serum concentration of Estazolam can be increased when it is combined with Itraconazole.
EtizolamThe serum concentration of Etizolam can be increased when it is combined with Itraconazole.
EtravirineThe serum concentration of Etravirine can be increased when it is combined with Itraconazole.
EverolimusThe serum concentration of Everolimus can be increased when it is combined with Itraconazole.
FamotidineThe serum concentration of Itraconazole can be decreased when it is combined with Famotidine.
FelodipineThe serum concentration of Felodipine can be increased when it is combined with Itraconazole.
FentanylThe serum concentration of Fentanyl can be increased when it is combined with Itraconazole.
FesoterodineThe serum concentration of the active metabolites of Fesoterodine can be increased when Fesoterodine is used in combination with Itraconazole.
FexofenadineThe serum concentration of Fexofenadine can be increased when it is combined with Itraconazole.
FlibanserinThe serum concentration of Flibanserin can be increased when it is combined with Itraconazole.
FluconazoleThe metabolism of Itraconazole can be decreased when combined with Fluconazole.
FludrocortisoneThe serum concentration of Fludrocortisone can be increased when it is combined with Itraconazole.
FlunarizineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Flunarizine.
FlunisolideThe serum concentration of Flunisolide can be increased when it is combined with Itraconazole.
Fluticasone PropionateThe serum concentration of Fluticasone Propionate can be increased when it is combined with Itraconazole.
FosamprenavirThe serum concentration of the active metabolites of Fosamprenavir can be increased when Fosamprenavir is used in combination with Itraconazole.
FosphenytoinThe serum concentration of Itraconazole can be decreased when it is combined with Fosphenytoin.
Fusidic AcidThe serum concentration of Itraconazole can be increased when it is combined with Fusidic Acid.
GabapentinThe risk or severity of adverse effects can be increased when Itraconazole is combined with Gabapentin.
GoserelinItraconazole may increase the QTc-prolonging activities of Goserelin.
GuanfacineThe serum concentration of Guanfacine can be increased when it is combined with Itraconazole.
HalofantrineThe serum concentration of Halofantrine can be increased when it is combined with Itraconazole.
HydrocodoneThe serum concentration of Hydrocodone can be increased when it is combined with Itraconazole.
IbrutinibThe serum concentration of Ibrutinib can be increased when it is combined with Itraconazole.
IdelalisibThe serum concentration of Itraconazole can be increased when it is combined with Idelalisib.
IfosfamideThe serum concentration of the active metabolites of Ifosfamide can be reduced when Ifosfamide is used in combination with Itraconazole resulting in a loss in efficacy.
IloperidoneThe serum concentration of the active metabolites of Iloperidone can be increased when Iloperidone is used in combination with Itraconazole.
ImatinibThe serum concentration of Imatinib can be increased when it is combined with Itraconazole.
ImidafenacinThe serum concentration of Imidafenacin can be increased when it is combined with Itraconazole.
IndinavirThe serum concentration of Indinavir can be increased when it is combined with Itraconazole.
IrinotecanThe serum concentration of the active metabolites of Irinotecan can be increased when Irinotecan is used in combination with Itraconazole.
IsavuconazoniumThe serum concentration of the active metabolites of Isavuconazonium can be increased when Isavuconazonium is used in combination with Itraconazole.
IsoniazidThe serum concentration of Itraconazole can be decreased when it is combined with Isoniazid.
IsradipineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Isradipine.
IvabradineThe serum concentration of Ivabradine can be increased when it is combined with Itraconazole.
IvacaftorThe serum concentration of Ivacaftor can be increased when it is combined with Itraconazole.
IxabepiloneThe serum concentration of Ixabepilone can be increased when it is combined with Itraconazole.
LacosamideThe serum concentration of Lacosamide can be increased when it is combined with Itraconazole.
LamotrigineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Lamotrigine.
LansoprazoleThe serum concentration of Itraconazole can be decreased when it is combined with Lansoprazole.
LapatinibThe serum concentration of Lapatinib can be increased when it is combined with Itraconazole.
LedipasvirThe serum concentration of Ledipasvir can be increased when it is combined with Itraconazole.
LercanidipineThe serum concentration of Lercanidipine can be increased when it is combined with Itraconazole.
LeuprolideItraconazole may increase the QTc-prolonging activities of Leuprolide.
LevobupivacaineThe serum concentration of Levobupivacaine can be increased when it is combined with Itraconazole.
LevomilnacipranThe serum concentration of Levomilnacipran can be increased when it is combined with Itraconazole.
LomitapideThe serum concentration of Lomitapide can be increased when it is combined with Itraconazole.
LopinavirThe serum concentration of Itraconazole can be increased when it is combined with Lopinavir.
LosartanThe metabolism of Losartan can be decreased when combined with Itraconazole.
LovastatinThe serum concentration of Lovastatin can be increased when it is combined with Itraconazole.
LuliconazoleThe serum concentration of Itraconazole can be increased when it is combined with Luliconazole.
LumacaftorThe serum concentration of Itraconazole can be decreased when it is combined with Lumacaftor.
LurasidoneThe serum concentration of Lurasidone can be increased when it is combined with Itraconazole.
MacitentanThe serum concentration of MACITENTAN can be increased when it is combined with Itraconazole.
Magnesium hydroxideThe serum concentration of Itraconazole can be decreased when it is combined with Magnesium hydroxide.
Magnesium oxideThe serum concentration of Itraconazole can be decreased when it is combined with Magnesium oxide.
Magnesium SulfateThe risk or severity of adverse effects can be increased when Itraconazole is combined with Magnesium Sulfate.
MaravirocThe serum concentration of Maraviroc can be increased when it is combined with Itraconazole.
Medroxyprogesterone acetateThe serum concentration of Medroxyprogesterone Acetate can be increased when it is combined with Itraconazole.
MeloxicamThe serum concentration of Meloxicam can be decreased when it is combined with Itraconazole.
MethadoneThe serum concentration of Methadone can be increased when it is combined with Itraconazole.
MethylergometrineThe serum concentration of Methylergometrine can be increased when it is combined with Itraconazole.
MethylprednisoloneThe serum concentration of Methylprednisolone can be increased when it is combined with Itraconazole.
MidazolamThe serum concentration of Midazolam can be increased when it is combined with Itraconazole.
MifepristoneThe serum concentration of Mifepristone can be increased when it is combined with Itraconazole.
MitotaneThe serum concentration of Itraconazole can be decreased when it is combined with Mitotane.
NaloxegolThe serum concentration of Naloxegol can be increased when it is combined with Itraconazole.
NelfinavirThe metabolism of Itraconazole can be decreased when combined with Nelfinavir.
NetupitantThe serum concentration of Itraconazole can be increased when it is combined with Netupitant.
NevirapineThe serum concentration of Itraconazole can be decreased when it is combined with Nevirapine.
NicardipineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Nicardipine.
NilotinibThe serum concentration of Nilotinib can be increased when it is combined with Itraconazole.
NimodipineThe serum concentration of Nimodipine can be increased when it is combined with Itraconazole.
NintedanibThe serum concentration of Nintedanib can be increased when it is combined with Itraconazole.
NisoldipineThe serum concentration of Nisoldipine can be increased when it is combined with Itraconazole.
NitrendipineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Nitrendipine.
NizatidineThe serum concentration of Itraconazole can be decreased when it is combined with Nizatidine.
OlaparibThe serum concentration of Olaparib can be increased when it is combined with Itraconazole.
OmeprazoleThe serum concentration of Itraconazole can be decreased when it is combined with Omeprazole.
OspemifeneThe serum concentration of Ospemifene can be increased when it is combined with Itraconazole.
OxybutyninThe serum concentration of Oxybutynin can be increased when it is combined with Itraconazole.
OxycodoneThe risk or severity of adverse effects can be increased when Itraconazole is combined with Oxycodone.
PalbociclibThe serum concentration of Palbociclib can be increased when it is combined with Itraconazole.
PaliperidoneItraconazole may increase the QTc-prolonging activities of Paliperidone.
PanobinostatThe serum concentration of Panobinostat can be increased when it is combined with Itraconazole.
PantoprazoleThe serum concentration of Itraconazole can be decreased when it is combined with Pantoprazole.
ParecoxibThe serum concentration of Parecoxib can be increased when it is combined with Itraconazole.
ParicalcitolThe serum concentration of Paricalcitol can be increased when it is combined with Itraconazole.
PazopanibThe serum concentration of Pazopanib can be increased when it is combined with Itraconazole.
PerhexilineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Perhexiline.
PhenobarbitalThe serum concentration of Itraconazole can be decreased when it is combined with Phenobarbital.
PhenytoinThe serum concentration of Itraconazole can be decreased when it is combined with Phenytoin.
PimecrolimusThe metabolism of Pimecrolimus can be decreased when combined with Itraconazole.
PimozideItraconazole may increase the arrhythmogenic activities of Pimozide.
PonatinibThe serum concentration of Ponatinib can be increased when it is combined with Itraconazole.
PranlukastThe serum concentration of Pranlukast can be increased when it is combined with Itraconazole.
PrasugrelThe serum concentration of the active metabolites of Prasugrel can be reduced when Prasugrel is used in combination with Itraconazole resulting in a loss in efficacy.
PravastatinThe serum concentration of Pravastatin can be increased when it is combined with Itraconazole.
PrednisoloneThe serum concentration of Prednisolone can be increased when it is combined with Itraconazole.
PrednisoneThe serum concentration of Prednisone can be increased when it is combined with Itraconazole.
PrenylamineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Prenylamine.
PrimidoneThe serum concentration of Itraconazole can be decreased when it is combined with Primidone.
PropafenoneThe serum concentration of Propafenone can be increased when it is combined with Itraconazole.
PrucaloprideThe serum concentration of Prucalopride can be increased when it is combined with Itraconazole.
QuetiapineThe serum concentration of Quetiapine can be increased when it is combined with Itraconazole.
QuinidineThe metabolism of Quinidine can be decreased when combined with Itraconazole.
RabeprazoleThe serum concentration of Itraconazole can be decreased when it is combined with Rabeprazole.
RamelteonThe serum concentration of Ramelteon can be increased when it is combined with Itraconazole.
RanitidineThe serum concentration of Itraconazole can be decreased when it is combined with Ranitidine.
RanolazineThe metabolism of Ranolazine can be decreased when combined with Itraconazole.
RegorafenibThe serum concentration of Regorafenib can be increased when it is combined with Itraconazole.
RepaglinideThe serum concentration of Repaglinide can be increased when it is combined with Itraconazole.
RetapamulinThe serum concentration of Retapamulin can be increased when it is combined with Itraconazole.
RifabutinThe serum concentration of Itraconazole can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Itraconazole can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Itraconazole can be decreased when it is combined with Rifapentine.
RifaximinThe serum concentration of Rifaximin can be increased when it is combined with Itraconazole.
RilpivirineThe serum concentration of Rilpivirine can be increased when it is combined with Itraconazole.
RiociguatThe serum concentration of Riociguat can be increased when it is combined with Itraconazole.
RisedronateThe risk or severity of adverse effects can be increased when Itraconazole is combined with Risedronate.
RitonavirThe serum concentration of Itraconazole can be increased when it is combined with Ritonavir.
RivaroxabanThe serum concentration of Rivaroxaban can be increased when it is combined with Itraconazole.
RomidepsinThe serum concentration of Romidepsin can be increased when it is combined with Itraconazole.
RosuvastatinThe serum concentration of Rosuvastatin can be increased when it is combined with Itraconazole.
RuxolitinibThe serum concentration of Ruxolitinib can be increased when it is combined with Itraconazole.
SalmeterolThe serum concentration of Salmeterol can be increased when it is combined with Itraconazole.
SaquinavirThe serum concentration of Saquinavir can be increased when it is combined with Itraconazole.
SaxagliptinThe serum concentration of Saxagliptin can be increased when it is combined with Itraconazole.
SildenafilThe serum concentration of Sildenafil can be increased when it is combined with Itraconazole.
SilodosinThe serum concentration of Silodosin can be increased when it is combined with Itraconazole.
SiltuximabThe serum concentration of Itraconazole can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Simeprevir can be increased when it is combined with Itraconazole.
SimvastatinThe serum concentration of Simvastatin can be increased when it is combined with Itraconazole.
SirolimusThe serum concentration of Sirolimus can be increased when it is combined with Itraconazole.
Sodium bicarbonateThe serum concentration of Itraconazole can be decreased when it is combined with Sodium bicarbonate.
SolifenacinThe metabolism of Solifenacin can be decreased when combined with Itraconazole.
SonidegibThe serum concentration of Sonidegib can be increased when it is combined with Itraconazole.
SorafenibThe serum concentration of Sorafenib can be increased when it is combined with Itraconazole.
St. John's WortThe serum concentration of Itraconazole can be decreased when it is combined with St. John's Wort.
StiripentolThe serum concentration of Itraconazole can be increased when it is combined with Stiripentol.
SucralfateSucralfate can cause a decrease in the absorption of Itraconazole resulting in a reduced serum concentration and potentially a decrease in efficacy.
SunitinibThe metabolism of Sunitinib can be decreased when combined with Itraconazole.
SuvorexantThe serum concentration of Suvorexant can be increased when it is combined with Itraconazole.
TacrolimusThe metabolism of Tacrolimus can be decreased when combined with Itraconazole.
TadalafilThe serum concentration of Tadalafil can be increased when it is combined with Itraconazole.
TamsulosinThe serum concentration of Tamsulosin can be increased when it is combined with Itraconazole.
TasimelteonThe serum concentration of Tasimelteon can be increased when it is combined with Itraconazole.
TelaprevirThe serum concentration of Itraconazole can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Telithromycin can be increased when it is combined with Itraconazole.
TemsirolimusThe serum concentration of the active metabolites of Temsirolimus can be increased when Temsirolimus is used in combination with Itraconazole.
TerfenadineThe serum concentration of Terfenadine can be increased when it is combined with Itraconazole.
TicagrelorThe serum concentration of the active metabolites of Ticagrelor can be reduced when Ticagrelor is used in combination with Itraconazole resulting in a loss in efficacy.
TipranavirThe serum concentration of Itraconazole can be increased when it is combined with Tipranavir.
TocilizumabThe serum concentration of Itraconazole can be decreased when it is combined with Tocilizumab.
TofacitinibThe serum concentration of Tofacitinib can be increased when it is combined with Itraconazole.
TolterodineThe serum concentration of Tolterodine can be increased when it is combined with Itraconazole.
TolvaptanThe serum concentration of Tolvaptan can be increased when it is combined with Itraconazole.
TopotecanThe serum concentration of Topotecan can be increased when it is combined with Itraconazole.
ToremifeneThe risk or severity of adverse effects can be increased when Itraconazole is combined with Toremifene.
TrabectedinThe serum concentration of Trabectedin can be increased when it is combined with Itraconazole.
TramadolThe serum concentration of Tramadol can be increased when it is combined with Itraconazole.
Trastuzumab emtansineThe serum concentration of the active metabolites of ado-trastuzumab emtansine can be increased when ado-trastuzumab emtansine is used in combination with Itraconazole.
TriazolamThe serum concentration of Triazolam can be increased when it is combined with Itraconazole.
UlipristalThe serum concentration of Ulipristal can be increased when it is combined with Itraconazole.
VardenafilThe serum concentration of Vardenafil can be increased when it is combined with Itraconazole.
VemurafenibThe serum concentration of Vemurafenib can be increased when it is combined with Itraconazole.
VerapamilThe serum concentration of Verapamil can be increased when it is combined with Itraconazole.
VilazodoneThe serum concentration of Vilazodone can be increased when it is combined with Itraconazole.
VinblastineThe serum concentration of Vinblastine can be increased when it is combined with Itraconazole.
VincristineThe serum concentration of Vincristine can be increased when it is combined with Itraconazole.
VindesineThe serum concentration of Vindesine can be increased when it is combined with Itraconazole.
VinorelbineThe risk or severity of adverse effects can be increased when Itraconazole is combined with Vinorelbine.
VorapaxarThe serum concentration of Vorapaxar can be increased when it is combined with Itraconazole.
WarfarinThe serum concentration of Warfarin can be increased when it is combined with Itraconazole.
ZolpidemThe serum concentration of Zolpidem can be increased when it is combined with Itraconazole.
ZopicloneThe serum concentration of Zopiclone can be increased when it is combined with Itraconazole.
ZuclopenthixolThe serum concentration of Zuclopenthixol can be increased when it is combined with Itraconazole.
Food Interactions
  • Avoid milk, calcium containing dairy products, iron, antacids, or aluminum salts 2 hours before or 6 hours after using antacids while on this medication.
  • Avoid taking with grapefruit juice.
  • Take after a full meal.
  • Take with food.

Targets

Kind
Protein
Organism
Yeast
Pharmacological action
yes
Actions
inhibitor
General Function:
Sterol 14-demethylase activity
Specific Function:
Catalyzes C14-demethylation of lanosterol which is critical for ergosterol biosynthesis. It transforms lanosterol into 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol (By similarity).
Gene Name:
ERG11
Uniprot ID:
P50859
Molecular Weight:
61304.95 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
  3. Gachotte D, Pierson CA, Lees ND, Barbuch R, Koegel C, Bard M: A yeast sterol auxotroph (erg25) is rescued by addition of azole antifungals and reduced levels of heme. Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11173-8. [PubMed:9326581 ]
  4. Henry KW, Nickels JT, Edlind TD: Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob Agents Chemother. 2000 Oct;44(10):2693-700. [PubMed:10991846 ]
  5. Morales IJ, Vohra PK, Puri V, Kottom TJ, Limper AH, Thomas CF Jr: Characterization of a lanosterol 14 alpha-demethylase from Pneumocystis carinii. Am J Respir Cell Mol Biol. 2003 Aug;29(2):232-8. Epub 2003 Feb 26. [PubMed:12606318 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
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
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
  2. Cotrim PC, Garrity LK, Beverley SM: Isolation of genes mediating resistance to inhibitors of nucleoside and ergosterol metabolism in Leishmania by overexpression/selection. J Biol Chem. 1999 Dec 31;274(53):37723-30. [PubMed:10608831 ]
  3. Carrillo-Munoz AJ, Giusiano G, Ezkurra PA, Quindos G: Antifungal agents: mode of action in yeast cells. Rev Esp Quimioter. 2006 Jun;19(2):130-9. [PubMed:16964330 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
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 xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Niwa T, Shiraga T, Takagi A: Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes. Biol Pharm Bull. 2005 Sep;28(9):1805-8. [PubMed:16141567 ]
  2. 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. [PubMed:15969931 ]
  3. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  4. Dresser GK, Spence JD, Bailey DG: Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000 Jan;38(1):41-57. [PubMed:10668858 ]
  5. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Oxygen binding
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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A5
Uniprot ID:
P20815
Molecular Weight:
57108.065 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Oxygen binding
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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP3A7
Uniprot ID:
P24462
Molecular Weight:
57525.03 Da
References
  1. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid 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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Molecular Weight:
56277.81 Da
References
  1. Walsky RL, Astuccio AV, Obach RS: Evaluation of 227 drugs for in vitro inhibition of cytochrome P450 2B6. J Clin Pharmacol. 2006 Dec;46(12):1426-38. [PubMed:17101742 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inducer
General Function:
Vitamin d 24-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 oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics.
Gene Name:
CYP1A1
Uniprot ID:
P04798
Molecular Weight:
58164.815 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic or carcinogenic forms.
Gene Name:
CYP2E1
Uniprot ID:
P05181
Molecular Weight:
56848.42 Da
References
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
inhibitor
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
References
  1. 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. [PubMed:11716514 ]
  2. 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. [PubMed:11751127 ]
  3. 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. [PubMed:12699389 ]
  4. Takara K, Tanigawara Y, Komada F, Nishiguchi K, Sakaeda T, Okumura K: Cellular pharmacokinetic aspects of reversal effect of itraconazole on P-glycoprotein-mediated resistance of anticancer drugs. Biol Pharm Bull. 1999 Dec;22(12):1355-9. [PubMed:10746169 ]
  5. Masuda S, Inui K: [Molecular mechanisms on drug transporters in the drug absorption and disposition]. Nihon Rinsho. 2002 Jan;60(1):65-73. [PubMed:11808341 ]
  6. 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. [PubMed:12621384 ]
  7. 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. [PubMed:15969931 ]
  8. 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. [PubMed:16041596 ]
  9. 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. [PubMed:16084853 ]
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Drug created on June 13, 2005 07:24 / Updated on July 26, 2016 01:53