Itraconazole

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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 namesSporanox
AHFS/Drugs.commonograph
MedlinePlusa692049
Pregnancy cat.C (safety unknown)
Legal statusPOM (UK) -only (US)
RoutesOral and i.v. (US), Oral only (UK)
Pharmacokinetic data
Bioavailability55%, maximal if taken with full meal
Protein binding99.8%
Metabolismhepatic (CYP3A4)
Half-life21 hours
Identifiers
CAS number84625-61-6 YesY
ATC codeJ02AC02
PubChemCID 55283
DrugBankDB01167
ChemSpider49927 YesY
UNII304NUG5GF4 YesY
KEGGD00350 YesY
ChEBICHEBI:6076 YesY
ChEMBLCHEMBL22587 YesY
Chemical data
FormulaC35H38Cl2N8O4 
Mol. mass705.64
 YesY (what is this?)  (verify)
 
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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 namesSporanox
AHFS/Drugs.commonograph
MedlinePlusa692049
Pregnancy cat.C (safety unknown)
Legal statusPOM (UK) -only (US)
RoutesOral and i.v. (US), Oral only (UK)
Pharmacokinetic data
Bioavailability55%, maximal if taken with full meal
Protein binding99.8%
Metabolismhepatic (CYP3A4)
Half-life21 hours
Identifiers
CAS number84625-61-6 YesY
ATC codeJ02AC02
PubChemCID 55283
DrugBankDB01167
ChemSpider49927 YesY
UNII304NUG5GF4 YesY
KEGGD00350 YesY
ChEBICHEBI:6076 YesY
ChEMBLCHEMBL22587 YesY
Chemical data
FormulaC35H38Cl2N8O4 
Mol. mass705.64
 YesY (what is this?)  (verify)

Itraconazole (R51211), invented in 1984, is a triazole antifungal agent prescribed to patients with fungal infections. The drug may be given orally or intravenously.

Medical uses[edit]

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 licensed for use in blastomycosis, sporotrichosis, 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 other antifungal drugs are inappropriate or ineffective. Itraconazole is currently being explored as an anticancer agent for patients with basal cell carcinoma, non-small cell lung cancer, and prostate cancer.[3]

Pharmacology[edit]

The mechanism of action of itraconazole is the same as the other azole antifungals: it inhibits the fungal-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 it is the only inhibitor in this class that has been shown to inhibit both the hedgehog signaling pathway[4][5] and angiogenesis.[6][7] 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,[7] trafficking,[8] and cholesterol biosynthesis pathways.[6] Evidence suggests the structural determinants for inhibition of hedgehog signaling by itraconazole are recognizably different from those associated with antiangiogenic activity.[9]

Formulation[edit]

The intravenous preparation is no longer available in the US as of October 11, 2007 per Ortho-Biotech Professional Letter but may be available in other countries. 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, itraconazole was found to contribute 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.[10] 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 with itraconazole:[citation needed]

Adverse effects[edit]

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.[11]

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

Production and marketing[edit]

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 brand 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.[12][13]

See also[edit]

Footnotes[edit]

  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. 
  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. ^ Kim, J; Aftab, BT; ...; Beachy, PB; Rudin, CM (2013). "Itraconazole and arsenic trioxide inhibit hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists". Cancer Cell 23 (1): 23–34. doi:10.1016/j.ccr.2012.11.017. PMC 3548977. PMID 23291299. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. PMID 20176935. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ a b "The Safety Of Sporanox Capsules And Lamisil Tablets For The Treatment Of Onychomycosis". FDA Public Health Advisory. May 9 2001. Archived from the original on 2009-05-28. Retrieved 2006-08-10. 
  12. ^ Composition comprising Itraconazole for oral administration. 2004. Fresh Patents.com. 26 October 2006.
  13. ^ Sporanox (Itraconazole Capsules). June 2006. Janssen. 26 October 2006

External links[edit]