Description
Itraconazole is an orally-active triazole antifungal indicated for use in the treatment of
dermal, vaginal and systemic mycoses. In immunocompromised and AIDS patients,
itraconazole has been shown to significantly reduce the incidence of relapses of
cryptococcal meningitis.
Originator
Janssen (Belgium)
Definition
ChEBI: Itraconazole is an N-arylpiperazine that is cis-ketoconazole in which the imidazol-1-yl group is replaced by a 1,2,4-triazol-1-yl group and in which the actyl group attached to the piperazine moiety is replaced by a p-[(+-)1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]phenyl group. A potent P-glycoprotein and CYP3A4 inhibitor, it is used as an antifungal drug for the treatment of various fungal infections, including aspergillosis, blastomycosis, candidiasis, chromoblastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and sporotrichosis. It has a role as a P450 inhibitor, an EC 3.6.3.44 (xenobiotic-transporting ATPase) inhibitor and a Hedgehog signaling pathway inhibitor. It is a member of triazoles, a dioxolane, a N-arylpiperazine, a dichlorobenzene, a cyclic ketal, a conazole antifungal drug, a triazole antifungal drug and an aromatic ether.
Indications
Itraconazole (Sporanox) is effective in the treatment of histoplasmosis, blastomycosis,
candidiasis, and dermatophyte infection. Its efficacy in the treatment
of tinea capitis in children is equal to griseofulvin, and it is usually better
tolerated (21). It is metabolized by the cytochrome P-450 system and may
increase the levels ofwarfarin, cyclosporine, and digoxin among others. Its use
is contraindicated with certain medications.
Itraconazole (Sporanox) is a triazole antifungal that is related to the imidazole
ketoconazole. Similar to ketoconazole, it interferes with ergosterol
synthesis and cell membrane integrity. It is clinically active against dimorphic
fungi, yeast, dermatophytes, Blastomycetes, histoplasmosis, sporotrichosis,
and Aspergillus.
Itraconazole is a potent inhibitor of the cytochrome P450 3A enzyme
system, which may elevate blood levels of other drugs metabolized by this system
if taken concomitantly. Itraconazole levels may decrease in patients who
are concurrently taking rifampin, phenobarbital, or phenytoin. Cyclosporine,
felodipine, digoxin, warfarin, and oral hypoglycemic levels may increase when
given in conjunction with itraconazole.
Itraconazole, like ketoconazole, is contraindicated in patients taking cisapride.
Itraconazole may induce torsades de pointes, ventricular arrhythmias,
and congestive heart failure.
Manufacturing Process
Synthesis of cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-
ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-
dihydro-2-(methylpropyl)-3H-1,2,4-triazol-3-one is showed by the same
procedure as for cis-4-{4-[4-{4-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-
ylmethyl)-1,3- dioxolan-4-ylmethoxy]phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-propyl-3H-1,2,4-triazol-3-one described in the patent.
A mixture of 13.4 parts of 1-(4-methoxyphenyl)piperazine dihydrochloride, 7.9
parts of 1-chloro-4-nitrobenzene, 10 parts of potassium carbonate and 90
parts of N,N-dimethylformamide is stirred and refluxed overnight. The reaction
mixture is diluted with water and the product is extracted twice with
trichloromethane. The residue is triturated in 4-methyl-2-pentanone. The
product is filtered off and crystallized from 1,4-dioxane, yielding 10.5 parts
(67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine; melting point
195.1°C.
A mixture of 12 parts of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)piperazine,
200 parts of methanol and 225 parts of tetrahydrofuran is hydrogenated at
normal pressure and at 20°C with 2 parts of palladium-on-charcoal catalyst
10%. After the calculated amount of hydrogen is taken up, the catalyst is
filtered off and washed with N,N-dimethylacetamide. Product is filtered off and
crystallized from 1-butanol, yielding 8 parts (74%) of 4-[4-(4-
methoxyphenyl)-1-piperazinyl]benzenamine; melting point 191.8°C.
A mixture of 30 parts of 4-[4-(4-methoxyphenyl)-1-piperazinyl]benzenamine
and 300 parts of a hydrobromic acid solution 48% in water is stirred and
refluxed for 10 days. The reaction mixture is evaporated and the residue is
alkalized with sodium hydroxide. The mixture is filtered and the filtrate is
acidified with acetic acid. The precipitated product is filtered off and
crystallized from 1,4-dioxane, yielding 12 parts (44%) of 2,4-dihydro-4-{4-[4-
(4-hydroxyphenyl)-1-piperazinyl]phenyl}-2-(1-methylpropyl)-3H-1,2,4-triazol-
3-one.
To a stirred solution of 2,4-dihydro-4-{4-[4-(4-hydroxyphenyl)-1-piperazinyl]
phenyl}-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one in 100 parts of dimethyl
sulfoxide are added 0.3 parts of sodium hydride dispersion 78% and the
whole is stirred at 50°C till foaming has ceased. Then there are added 3.7
parts of cis-[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-
dioxolan-4-ylmethyl]methanesulfonate and stirring is continued for 3 hours at
100°C. The reaction mixture is cooled and poured onto water. The product is
extracted with dichloromethane. The extracts are washed with a diluted
sodium hydroxide solution and filtered. The residue is crystallized from 1-
butanol. The product yield 4.3 parts (75%) of cis-4-{4-[4-{4-[2-(2,4-
dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]
phenyl}-1-piperazinyl]phenyl}-2,4-dihydro-2-(methylpropyl)-3H-1,2,4-triazol-
3-one.
Brand name
Sporanox (Janssen).
Therapeutic Function
Antifungal
Antimicrobial activity
The spectrum includes dermatophytes, dimorphic fungi
(Blast. dermatitidis, Coccidioides spp., Hist. capsulatum, Paracocc.
brasiliensis,
Penicillium marneffei and Spor. schenckii), molds
(including Aspergillus spp.), dematiaceous fungi and yeasts
(Candida spp. and Cryptococcus spp.).
Acquired resistance
This is uncommon, but fluconazole-resistant C. albicans and
C. glabrata are often cross-resistant to itraconazole. There are
reports of itraconazole-resistant strains of A. fumigatus.
General Description
Itraconazole is an antifungal drug prescribed for oral or intravenous treatment of fungal infections. The drug is sold under trade names such as Sporanoxor Onmel?. This Certified Spiking Solution? is suitable as starting material for calibrators, controls, or linearity standards for clinical and diagnostic testing or therapeutic drug monitoring of itraconazole in patient blood, serum, or plasma samples by LC-MS/MS or HPLC.
Pharmaceutical Applications
A synthetic dioxolane triazole available for oral or parenteral
administration.
Biochem/physiol Actions
Itraconazole inhibits cytochrome P-450-dependent enzymes which results in the inhibition of ergosterol synthesis. It does so by interacting with 14-α demethylase, which is a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. Ergosterol is a crucial compenent of fungal cell membranes. Therefore, it′s inhibition 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 phospholipid biosynthesis.
Clinical Use
Aspergillosis
Systemic mycoses with dimorphic fungi (blastomycosis,
coccidioidomycosis, histoplasmosis, paracoccidioidomycosis, penicilliosis)
Subcutaneous mycoses (chromoblastomycosis, sporotrichosis)
Mucosal and cutaneous candidosis.
Dermatophytosis
Phaeohyphomycosis
Pityriasis versicolor
Side effects
Unwanted effects are more common with oral solution than
with capsules, and are more severe. They include nausea,
abdominal discomfort, dyspepsia, diarrhea, headache, pruritus
and skin rash. Rare side effects include Stevens–Johnson
syndrome, transient abnormalities of liver enzymes, reversible
idiosyncratic hepatitis and hypokalemia.
Intravenous itraconazole has been associated with congestive
heart failure. Neither intravenous nor oral itraconazole should
be used to treat infections in patients with evidence of ventricular
dysfunction unless the expected benefit clearly exceeds
the risk. Patients with risk factors for congestive heart failure
should be treated with caution and their condition monitored.
Veterinary Drugs and Treatments
Itraconazole may have use in veterinary medicine in the treatment
of systemic mycoses, including aspergillosis, cryptococcal meningitis,
blastomycosis, and histoplasmosis. Itraconazole
is probably
more effective than ketoconazole, but is significantly more expensive.
It may also be useful for superficial candidiasis or dermatophytosis，Itraconazole does not have appreciable effects (unlike ketoconazole)
on hormone synthesis and may have fewer side effects
than ketoconazole in small animals.
It is considered by many to be the drug of choice for treating
blastomycosis, unless moderate or severe
hypoxemia is present
(than amphotericin B).
In horses, itraconazole may be useful in the treatment of sporotrichosis
and Coccidioides immitis osteomyelitis.
in vitro
itraconazole was metabolized into hydroxy-itraconazole (oh-itz), a known in vivo metabolite of itz, and two new metabolites: keto-itraconazole (keto-itz) and n-desalkyl-itraconazole (nd-itz). itraconazole was a substrate for cyp3a and to characterize the metabolites generated. itraconazole exhibited an unbound km of 3.9 nm for cyp3a. itraconazole metabolites are as potent as or more potent cyp3a4 inhibitors than itz itself [1]. itraconazole was pharmacologically distinct from other azole antifungal agents. itraconazole has been shown to inhibit both the hedgehog signaling pathway and angiogenesis [2] itraconazole was active against 60 clinical isolates of aspergillus spp. with geometric mean (gm) mics of 0.25 mg/ml [3]. itraconazoleshowed an affinity for mammalian cytochrome p-450 enzymes as well as for fungal p-450-dependent enzyme, and thus has the potential for clinically important interactions [4].
in vivo
oral administration of itraconazole (200 mg) once daily for 4 days increased the area under the midazolam concentration-time curve from 10 to 15 times (p < 0.001) and mean peak concentrations three to four times (p < 0.001) compared with the placebo phase [5].
Drug interactions
Potentially hazardous interactions with other drugs Aliskiren: concentration of aliskiren increased - avoid Analgesics: possibly inhibits alfentanil metabolism; concentration of fentanyl possibly increased; possibly increases methadone concentration - increased risk of ventricular arrhythmias. Anti-arrhythmics: avoid concomitant use with disopyramide and dronedarone. Antibacterials: metabolism accelerated by rifabutin and rifampicin - avoid; possibly increased rifabutin concentration - reduce rifabutin dose; clarithromycin can increase itraconazole concentration. Anticoagulants: avoid with apixiban and rivaroxaban; effect of coumarins enhanced; concentration of dabigatran possibly increased - avoid. Antidepressants: avoid concomitant use with reboxetine. Antidiabetics: can enhance effects of repaglinide. Antiepileptics: concentration reduced by carbamazepine, fosphenytoin, phenobarbital and phenytoin - avoid with phenytoin. Antihistamines: inhibits mizolastine metabolism - avoid. Antimalarials: avoid with piperaquine with artenimol and artemether/lumefantrine. Antimuscarinics: possibly increases solifenacin concentration. Antipsychotics: possibly increases haloperidol concentration; possibly inhibits metabolism of aripiprazole - reduce aripiprazole dose; increased risk of ventricular arrhythmias with pimozide - avoid; possibly increased quetiapine concentration - reduce quetiapine dose; possibly increases lurasidone concentration - avoid. Antivirals: concentration of daclatasvir increased - reduce daclatasvir dose; concentration of both drugs increased with dasabuvir, paritaprevir and simeprevir - avoid; concentration reduced by efavirenz and nevirapine; concentration of both drugs possibly increased by fosamprenavir; concentration of indinavir increased - may need to reduce indinavir dose; with ritonavir concentration of both drugs may be increased; concentration of saquinavir possibly increased; concentration possibly increased by telaprevir; concentration reduced by efavirenz. Anxiolytics and hypnotics: concentration of buspirone, midazolam and alprazolam increased - reduce buspirone dose.
Metabolism
Itraconazole is metabolised in the liver mainly by
cytochrome P450 isoenzyme CYP3A4. The major
metabolite, hydroxyitraconazole, has antifungal activity
comparable with that of itraconazole.
Itraconazole is excreted mainly as inactive metabolites
in urine (35%) and faeces (54%) within one week of an
oral solution dose. Renal excretion of itraconazole and
the active metabolite hydroxy-itraconazole account for
less than 1% of an intravenous dose. Based on an oral
radiolabelled dose, faecal excretion of unchanged drug
varies between 3-18% of the dose. Small amounts are
eliminated in the stratum corneum and hai
References
1) Vanden Bossche?et al.?(1993),?Effects of itraconazole on cytochrome P-450-dependent sterol 14 alpha-demethylation and reduction of 3-ketosteroids in Cryptococcus neoformans; Antimicrob. Agents Chemother.,?37?2101
2) Liu?et al.?(2014),?Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking; Autophagy,?10?1241
3) Kim?et al. (2010),?Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth; Cancer Cell,?17?388
4) Nacev?et al. (2011),?The antifungal drug itraconazole inhibits vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, trafficking, and signaling in endothelial cells; J. Biol. Chem.,?286?44045
