Itraconazole

Itraconazole

Systematic (IUPAC) name
(2R,4S)-rel-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
Clinical data
Trade names	Sporanox
AHFS/Drugs.com	monograph
MedlinePlus	a692049
Pregnancy cat.	C (safety unknown)
Legal status	POM (UK) ℞-only (US)
Routes	Oral and i.v. (US), Oral only (UK)
Pharmacokinetic data
Bioavailability	55%, maximal if taken with full meal
Protein binding	99.8%
Metabolism	hepatic (CYP3A4)
Half-life	21 hours
Identifiers
CAS number	84625-61-6 Y
ATC code	J02AC02
PubChem	CID 55283
DrugBank	APRD00040
ChemSpider	49927 Y
UNII	304NUG5GF4 Y
KEGG	D00350 Y
ChEBI	CHEBI:6076 Y
ChEMBL	CHEMBL22587 Y
Chemical data
Formula	C35H38Cl2N8O4
Mol. mass	705.64
SMILES	eMolecules & PubChem
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 Y Key:VHVPQPYKVGDNFY-ZPGVKDDISA-N Y
N(what is this?)  (verify)

Itraconazole (marketed as Sporanox by Janssen Pharmaceutica), invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.

Medical uses

Itraconazole has a broader spectrum of activity than fluconazole (but not as broad as voriconazole or posaconazole). In particular, it is active against Aspergillus, which fluconazole is not. It is also licenced for use in blastomycosis, histoplasmosis and onychomycosis. Itraconazole is over 99% protein bound and has virtually no penetration into cerebrospinal fluid. Therefore, it should never be used to treat meningitis or other central nervous system infections.^[1] According to the Johns Hopkins Abx Guide, it has "negligible CSF penetration, however treatment has been successful for cryptococcal and coccidioidal meningitis".^[2]

It is also prescribed for systemic infections such as aspergillosis, candidiasis and cryptococcosis where otherantifungal drugs are inappropriate or ineffective. Itraconazole is currently being explored as an anti-cancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer.^[3]

Pharmacology

The mechanism of action of itraconazole is the same as the other azole antifungals: it inhibits the fungal cytochrome P450 oxidase-mediated synthesis of ergosterol. Because of its ability to inhibit cytochrome P450 3A4 CC-3, caution should be used when considering interactions with other medications.^{[citation needed]}

Itraconazole is pharmacologically distinct from other azole antifungal agents in that itraconazole is the only inhibitor in this class that has been shown to inhibit both the hedgehog signaling pathway.^[4] and angiogenesis^[5][6] These distinct activities are unrelated to inhibition of the cytochrome P450 Lanosterol 14 alpha-demethylase and the exact molecular targets responsible remain unidentified. Functionally, the antiangiogenic activity of itraconazole has been shown to be linked to inhibition of glycosylation, VEGFR2 phosphorylation,^[6] trafficking,^[7] and cholesterol biosynthesis pathways.^[5] Evidence suggests that structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with anti-angiogenic activity.^[8]

Formulation

There is an intravenous preparation available in the US, but not in the UK. In the UK, if an intravenous preparation is required, then an alternative antifungal drug should be used.^{[citation needed]}

Itraconazole has relatively low bioavailability after oral administration, especially when given in capsule form on an empty stomach. The capsule form is a molecular dispersion of itraconazole in amorphous HPMC polymer. The fast dissolving polymer targets a supersaturated solution of itraconazole from which enhanced absorption can be expected. Recently, it was evidenced that itraconazole contributes to the formation of nanofibers in certain simulated intestinal fluids. These nanofibers have a uniform width of 12 nm and a length up to several micrometers.^[9] The oral solution is better absorbed. The cyclodextrin contained in the oral solution can cause an osmotic diarrhea, and if this is a problem, then half the dose can be given as oral solution and half as capsule to reduce the amount of cyclodextrin given. Itraconazole capsules should always be taken with food, as this improves absorption. Itraconazole oral solution should be taken an hour before food, or two hours after food (and likewise if a combination of capsules and oral solution are used). Itraconazole may be taken with orange juice or cola, as absorption is also improved by acid. Absorption of itraconazole is impaired when taken with an antacid, H₂-blocker or proton pump inhibitor.^{[citation needed]}

The following drugs should not be taken together with itraconazole:^{[citation needed]}

• cisapride (Propulsid);
• dofetilide (Tikosyn);
• nisoldipine (Sular);
• pimozide (Orap);
• quinidine (Quinaglute, Quinidex, Quin-Release);
• lovastatin (Altocor, Altoprev, Mevacor) or simvastatin (Zocor);
• midazolam (Versed) or triazolam (Halcion);
• ergot medicines such as dihydroedrgotamine (D.H.E. 45, Migranal), ergonavine (Ergotrate), ergotamine (Ergomar, Cafergot, Ercaf, Migergot), or methylergonovine (Methergine).

Adverse effects

Itraconazole is a relatively well-tolerated drug (although not as well tolerated as fluconazole or voriconazole) and the range of adverse effects it produces is similar to the other azole antifungals.^[10]

• Elevated alanine aminotransferase levels is found in 4% of people taking itraconazole
• "Small but real risk" of developing congestive heart failure^[10]
• Liver failure, sometimes fatal

The cyclodextrin that is used to make the syrup preparation can cause diarrhea. Side-effects that may indicate a greater problem include:

• nausea
• vomiting
• abdominal pain
• fatigue
• loss of appetite
• yellow skin (jaundice)
• yellow eyes
• itching
• dark urine
• pale stool

Production and marketing

Itraconazole is produced as blue 22 mm (0.87 in) capsules with tiny 1.5 mm (0.059 in) blue pellets inside. Each capsule contains 100 mg and is usually taken twice a day i.e. every twelve hours. The Sporanox the brand name of itraconazole has been developed and marketed by Janssen Pharmaceutica, a subsidiary of Johnson & Johnson. The three layer structure of these blue capsules are complex because itraconazole is insoluble and is sensitive to pH. The complicated procedure not only requires a specialized machine to create it, but also the method used has manufacturing problems. Also, the pill is quite large, making it difficult for many patients to swallow. Parts of the processes of creating Sporanox were discovered by the Korean Patent Laid. The contents of the capsule, the tiny blue pellets, are manufactured in Beerse, Belgium.^[11][12]

See also

• Fluconazole
• Lanosterol 14 alpha-demethylase

Footnotes

1. ^ Gilbert DN, Moellering, RC, Eliopoulos GM, Sande MA (2006). The Sanford Guide to antimicrobial therapy. ISBN 1-930808-30-5. ^{[page needed]}
2. ^ Pham, P; Bartlett, JG (2007-07-24). "Itraconazole". Johns Hopkins. http://www.hopkins-abxguide.org/terminals/antibiotics_more.cfm?id=81&fc=p. 
3. ^ clinicaltrials.gov
4. ^ Kim, James; Tang, Jean Y.; Gong, Ruoyu; Kim, Jynho; Lee, John J.; Clemons, Karl V.; Chong, Curtis R.; Chang, Kris S. et al. (2010). "Itraconazole, a Commonly Used Antifungal that Inhibits Hedgehog Pathway Activity and Cancer Growth". Cancer Cell 17 (4): 388–99. doi:10.1016/j.ccr.2010.02.027. PMID 20385363. 
5. ^ ^{a b} Chong, Curtis R.; Xu, Jing; Lu, Jun; Bhat, Shridhar; Sullivan, David J.; Liu, Jun O. (2007). "Inhibition of Angiogenesis by the Antifungal Drug Itraconazole". ACS Chemical Biology 2 (4): 263–70. doi:10.1021/cb600362d. PMID 17432820. 
6. ^ ^{a b} Aftab, B. T.; Dobromilskaya, I.; Liu, J. O.; Rudin, C. M. (2011). "Itraconazole Inhibits Angiogenesis and Tumor Growth in Non-Small Cell Lung Cancer". Cancer Research 71 (21): 6764–72. doi:10.1158/0008-5472.CAN-11-0691. PMC 3206167. PMID 21896639. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3206167. 
7. ^ Xu, J.; Dang, Y.; Ren, Y. R.; Liu, J. O. (2010). "Cholesterol trafficking is required for mTOR activation in endothelial cells". Proceedings of the National Academy of Sciences 107 (10): 4764–9. doi:10.1073/pnas.0910872107. PMC 2842052. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2842052. 
8. ^ Shi, Wei; Nacev, Benjamin A.; Aftab, Blake T.; Head, Sarah; Rudin, Charles M.; Liu, Jun O. (2011). "Itraconazole Side Chain Analogues: Structure–Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling". Journal of Medicinal Chemistry 54 (20): 7363–74. doi:10.1021/jm200944b. PMID 21936514. 
9. ^ Mellaerts, Randy; Aerts, Alexander; Caremans, Tom P.; Vermant, Jan; Van Den Mooter, Guy; Martens, Johan A.; Augustijns, Patrick (2010). "Growth of Itraconazole Nanofibers in Supersaturated Simulated Intestinal Fluid". Molecular Pharmaceutics 7 (3): 905–13. doi:10.1021/mp900300j. PMID 20232903. 
10. ^ ^{a b} "The Safety Of Sporanox Capsules And Lamisil Tablets For The Treatment Of Onychomycosis". FDA Public Health Advisory. May 9 2001. http://www.fda.gov/CDER/drug/advisory/sporanox-lamisil/advisory.htm. Retrieved 2006-08-10. ^{[dead link]}
11. ^ Composition comprising Itraconazole for oral administration. 2004. Fresh Patents.com. 26 October 2006.
12. ^ Sporanox (Itraconazole Capsules). June 2006. Janssen. 26 October 2006

External links

• General pharmacologic information about itraconazole
• Treatment of aseptic meningitis