13 DE LEON, QUENNIE FAE F.

Identification Name Accession Number Type Groups Itraconazole DB01167 (APRD00040) small molecule approved

2A PHARMACY

One of the triazole antifungal agents that inhibits cytochrome P-450dependent enzymes resulting in impairment of ergosterol synthesis. It has been Description used against histoplasmosis, blastomycosis, cryptococcal meningitis & aspergillosis.

Structure

ITC ITCZ Synonyms Itraconazol [Spanish] Itraconazolum [Latin] ITZ Antifungals Categories Antiprotozoals Antifungal Agents Antiprotozoal Agents CAS number Weight Chemical Formula IUPAC Name 84625-61-6 Average: 705.633 Monoisotopic: 704.239307158 C35H38Cl2N8O4 1-(butan-2-yl)-4-{4-[4-(4-{[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazin-1-yl]phenyl}-4,5-dihydro1H-1,2,4-triazol-5-one SMILES Taxonomy Kingdom Organic CCC(C)N1N=CN(C1=O)C1=CC=C(C=C1)N1CCN(CC1)C1=CC=C(OC[C@H]2CO[C @@](CN3C=NC=N3)(O2)C2=C(Cl)C=C(Cl)C=C2)C=C1

 Benzyl Alcohols and Derivatives Phenols and Derivatives Classes Ethers Phenethylamines Anisoles Glycerol and Derivatives Benzyl Alcohols and Derivatives Acetals and Derivatives Triazoles Phenols and Derivatives Aliphatic and Aryl Amines Piperazines Ethers Benzene and Derivatives Substructures Aryl Halides Halobenzenes Dioxoles Phenethylamines Heterocyclic compounds Aromatic compounds Anisoles Cyanamides Phenyl Esters Anilines Pharmacology For the treatment of the following fungal infections in immunocompromised Indication and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis. Itraconazole is an imidazole/triazole type antifungal agent. Itraconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 demethylation via the inhibition of the enzyme cytochrome P450 14demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell wall synthesis. The subsequent loss of normal sterols correlates with
Pharmacodynamics

the accumulation of 14 -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 Itraconazole interacts with 14- demethylase, a cytochrome P-450 enzyme

action

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. The absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal. 796 185 L 99.8% 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 1methylpropyl substituent, oxidative degradation of the piperazine ring and triazolone scission. 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.

Absorption Volume of distribution Protein binding

Metabolism

Route of elimination

Half life Clearance Toxicity Affected organisms Pathways

21 hours 381 +/- 95 mL/minute [IV administration] 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. Fungi, yeast and protozoans oral or intravenous

Source: http://www.drugbank.ca/drugs/DB01167