PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
itraconazole

2D structure

Overview

Generic Names: ITC; ITCZ; ITR; ITZ; Itraconazol [Spanish]; Itraconazolum [Latin]; itraconazole
Trade Names: Hyphanox; Itrizole; Oriconazole; Sporal; Sporanos; Sporanox; Sporonox; Triasporn
PharmGKB Accession Id: PA450132

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 (source: Drug Bank)

Indication

For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis. (source: Drug Bank)

ATC Therapeutic Category

  • J02AC:Triazole derivatives

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

Itraconazole 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. (source: Drug Bank)

Pharmacology

Itraconazole 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 <i>in vitro</i> activity against <i>Cryptococcus neoformans</i> and <i>Candida spp.</i> Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to <i>Cryptococcus neoformans</i> and for systemic infections due to <i>Candida albicans</i>. (source: Drug Bank)

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. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

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. (source: Drug Bank)

Protein Binding

99.8% (source: Drug Bank)

Absorption

The absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal. (source: Drug Bank)

Toxicity

No 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. (source: Drug Bank)

Isomeric SMILES Code:

CC[C@@H](C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OC[C@H]5CO[C@](O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl (source: Drug Bank)

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
  •   
  • PD
  • PK
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C19
  •   
  •   
  •   
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP2C8
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  •   
  •   
  • PK
  •   
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP2E1
  •   
  •   
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  •   
  • PD
  • PK
  •   
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Has annotations
SLCO1B1
  •   
  • PD
  • PK
  •   
  •   
Publications

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene Description
ABCB1 Uncurated Annotation (source: Drug Bank)
CYP51A1 Uncurated Annotation (source: Drug Bank)

A list of non-curated publications that mention this drug along with other drugs is available.

Drug Interactions

Drug Description
acenocoumarol Uncurated Annotation The imidazole increases the effect of the anticoagulant (source: Drug Bank)
alfentanil Uncurated Annotation The imidazole increases the effect and toxicity of alfentanil (source: Drug Bank)
almotriptan Uncurated Annotation This potent CYP3A4 inhibitor increases the effect and toxicity of the triptan (source: Drug Bank)
alprazolam Uncurated Annotation The imidazole increases the effect of the benzodiazepine (source: Drug Bank)
aripiprazole Uncurated Annotation The imidazole increases the effect of aripiprazole (source: Drug Bank)
astemizole Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
atorvastatin Uncurated Annotation Increased risk of myopathy/rhabdomyolysis (source: Drug Bank)
bosentan Uncurated Annotation The imidazole increases the effect and toxicity of bosentan (source: Drug Bank)
budesonide Uncurated Annotation The imidazole increases levels/effect of budesonide (source: Drug Bank)
buspirone Uncurated Annotation The macrolide increases the effect and toxicity of buspirone (source: Drug Bank)
calcium Uncurated Annotation The antacid decreases the effect of the imidazole (source: Drug Bank)
carbamazepine Uncurated Annotation The imidazole increases the effect of carbamazepine (source: Drug Bank)
cerivastatin Uncurated Annotation Increased risk of myopathy/rhabdomyolysis (source: Drug Bank)
chlordiazepoxide Uncurated Annotation The imidazole increases the effect of the benzodiazepine (source: Drug Bank)
cimetidine Uncurated Annotation The anti-H2 decreases the absorption of the imidazole (source: Drug Bank)
cisapride Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
clarithromycin Uncurated Annotation The macrolide increases the effect and toxicity of itraconazole (source: Drug Bank)
clonazepam Uncurated Annotation The imidazole increases the effect of the benzodiazepine (source: Drug Bank)
cyclosporine Uncurated Annotation The imidazole increases the effect of the immunosuppressant (source: Drug Bank)
diazepam Uncurated Annotation The imidazole increases the effect of the benzodiazepine (source: Drug Bank)
dicumarol Uncurated Annotation The imidazole increases the effect of the anticoagulant (source: Drug Bank)
digoxin Uncurated Annotation Itraconazole increases the effect of digoxin (source: Drug Bank)
dofetilide Uncurated Annotation This strong CYP3A4 inhibitor increases the effect and toxicity of dofetilide (source: Drug Bank)
eletriptan Uncurated Annotation This potent CYP3A4 inhibitor increases the effect and toxicity of the triptan (source: Drug Bank)
erlotinib Uncurated Annotation This potent CYP3A4 inhibitor increases levels/toxicity of erlotinib (source: Drug Bank)
erythromycin Uncurated Annotation The macrolide increases the effect and toxicity of itraconazole (source: Drug Bank)
esomeprazole Uncurated Annotation The proton pump inhibitor decreases the absorption of imidazole (source: Drug Bank)
estazolam Uncurated Annotation The imidazole increases the effect of the benzodiazepine (source: Drug Bank)
ethinyl estradiol Uncurated Annotation This anti-infectious agent could decreases the effect of the oral contraceptive (source: Drug Bank)
famotidine Uncurated Annotation The anti-H2 decreases the absorption of the imidazole (source: Drug Bank)
felodipine Uncurated Annotation Increases effect/toxicity of felodipine (source: Drug Bank)
fentanyl Uncurated Annotation The imidazole increases levels/toxicity of fentanyl (source: Drug Bank)
flurazepam Uncurated Annotation The imidazole increases the effect of the benzodiazepine (source: Drug Bank)
gefitinib Uncurated Annotation This potent CYP3A4 inhibitor increases levels/toxicity of gefitinib (source: Drug Bank)
haloperidol Uncurated Annotation The imidazole increases the effect and toxicity of haloperidol (source: Drug Bank)
imatinib Uncurated Annotation The imidazole increases the levels of imatinib (source: Drug Bank)
lansoprazole Uncurated Annotation The proton pump inhibitor decreases the absorption of imidazole (source: Drug Bank)
levomethadyl acetate Uncurated Annotation Itraconazole increases the effect/toxicity of levomethadyl (source: Drug Bank)
lovastatin Uncurated Annotation Increased risk of myopathy/rhabdomyolysis (source: Drug Bank)
magnesium Uncurated Annotation The antacid decreases the effect of the imidazole (source: Drug Bank)
magnesium oxide Uncurated Annotation The antacid decreases the effect of the imidazole (source: Drug Bank)
mephenytoin Uncurated Annotation Phenytoin decreases the effect of itraconazole (source: Drug Bank)
mestranol Uncurated Annotation This anti-infectious agent could decrease the effect of the oral contraceptive (source: Drug Bank)
methylprednisolone Uncurated Annotation The imidazole increases the effect and toxicity of the corticosteroid (source: Drug Bank)
midazolam Uncurated Annotation The imidazole increases the effect of the benzodiazepine (source: Drug Bank)
omeprazole Uncurated Annotation The proton pump inhibitor decreases the absorption of imidazole (source: Drug Bank)
pantoprazole Uncurated Annotation The proton pump inhibitor decreases the absorption of imidazole (source: Drug Bank)
phenobarbital Uncurated Annotation The barbiturate decreases the effect of itraconazole (source: Drug Bank)
phenytoin Uncurated Annotation Phenytoin decreases the effect of itraconazole (source: Drug Bank)
pimozide Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
prednisolone Uncurated Annotation The imidazole increases the effect and toxicity of the corticosteroid (source: Drug Bank)
prednisone Uncurated Annotation The imidazole increases the effect and toxicity of the corticosteroid (source: Drug Bank)
quinidine Uncurated Annotation The imidazole increases the effect and toxicity of quinidine (source: Drug Bank)
rabeprazole Uncurated Annotation The proton pump inhibitor decreases the absorption of imidazole (source: Drug Bank)
ranitidine Uncurated Annotation The anti-H2 decreases the absorption of the imidazole (source: Drug Bank)
rifabutin Uncurated Annotation Rifabutin decreases the effect of itraconazole (source: Drug Bank)
rifampin Uncurated Annotation Rifampin decreases the effect of the imidazole (source: Drug Bank)
risperidone Uncurated Annotation Increases the level of risperidone (source: Drug Bank)
ritonavir Uncurated Annotation The imidazole increases the effect and toxicity of ritonavir (source: Drug Bank)
sildenafil Uncurated Annotation The imidazole increases the effect and toxicity of sildenafil (source: Drug Bank)
simvastatin Uncurated Annotation Increased risk of myopathy/rhabdomyolysis (source: Drug Bank)
simvastatin Uncurated Annotation Increased risk of myopathy/rhabdomyolysis (source: Drug Bank)
sirolimus Uncurated Annotation The imidazole increases the effect and toxicity of sirolimus (source: Drug Bank)
sucralfate Uncurated Annotation Sucralfate decreases the absorption of the imidazole (source: Drug Bank)
sunitinib Uncurated Annotation Possible increase in sunitinib levels (source: Drug Bank)
tacrolimus Uncurated Annotation The imidazole increases the effect of immunosuppressant (source: Drug Bank)
terfenadine Uncurated Annotation Increased risk of cardiotoxicity and arrhythmias (source: Drug Bank)
trazodone Uncurated Annotation This potent CYP3A4 inhibitor increases the effect and toxicity of trazodone (source: Drug Bank)
triazolam Uncurated Annotation The imidazole increases the effect of the benzodiazepine (source: Drug Bank)
vardenafil Uncurated Annotation The imidazole increases the effect and toxicity of vardenafil (source: Drug Bank)
vinblastine Uncurated Annotation The imidazole increases the effect and toxicity of the antineoplasic (source: Drug Bank)
vincristine Uncurated Annotation The imidazole increases the effect and toxicity of the antineoplasic (source: Drug Bank)
warfarin Uncurated Annotation The imidazole increases the effect of the anticoagulant (source: Drug Bank)

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Carotid Artery Diseases
  •   
  • PD
  • PK
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Neutropenia
  • CO
  •   
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Rhabdomyolysis
  •   
  • PD
  • PK
  •   
  •   
Publications

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

  1. Drug-Induced Long QT Intervals
    • Genotype data available
    • Phenotype data available
    • No literature annotations
    • Not annotated
    • PD
    Submitted by Dan Roden, MD involving ADRB1, ADRB2, KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A, almokalant, amiodarone, amitriptyline, bretylium, bupivacaine, cisapride, disopyramide, dofetilide, encainide, fluconazole, haloperidol, hydroquinidine, isoflurane, itraconazole, ketoconazole, lithium, loratadine, metoclopramide, nortriptyline, procainamide, quinidine, sematilide, sotalol, sulfamethoxazole, thioridazine, trimethoprim, , Long QT Syndrome, Proarrhythmia and Torsades de Pointes

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. Physicochemical determinants of human renal clearance

Downloads

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LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB01167
KEGG Drug ID:
D00350
PubChem Compound ID:
55283
PubChem Substance ID:
192757

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

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