Absorption, Distribution and Excretion
Itraconazole is rapidly absorbed after oral administration. As oral capsules, peak plasma concentrations of itraconazole are reached within two to five hours. The observed absolute oral bioavailability of itraconazole is about 55%. Itraconazole exposure is lower with the capsule formulation than with the oral solution when the same dose of the drug is given. Maximal drug absorption is achieved under adequate gastric acidity. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma during multiple dosing. Steady-state concentrations are generally reached within about 15 days, with Cmax values of 0.5 μg/mL, 1.1 μg/mL and 2.0 μg/mL after oral administration of 100 mg once daily, 200 mg once daily and 200 mg b.i.d., respectively.
Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%) within one week of an oral solution dose. Renal excretion of itraconazole and the active metabolite hydroxyitraconazole account for less than 1% of an intravenous dose. Based on an oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose. As the re-distribution of itraconazole from keratinous tissues appears to be negligible, the elimination of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the concentration in skin persists for two to four weeks after discontinuation of a 4-week treatment and in nail keratin – where itraconazole can be detected as early as one week after the start of treatment – for at least six months after the end of a 3-month treatment period.
The volume of distribution is more than 700 L in adults. Itraconazole is lipophilic and extensively distributed into tissues. Concentrations in the lung, kidney, liver, bone, stomach, spleen and muscle were found to be two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.
The mean total plasma clearance following intravenous administration is 278 mL/min. Itraconazole clearance decreases at higher doses due to saturable hepatic metabolism.
The pharmacokinetics of itraconazole after intravenous administration and its absolute oral bioavailability from an oral solution were studied in a randomized crossover study in 6 healthy male volunteers. The observed absolute oral bioavailability of itraconazole was 55%.
The oral bioavailability of itraconazole is maximal when itraconazole capsules are taken with a full meal. The pharmacokinetics of itraconazole were studied in 6 healthy male volunteers who received, in a crossover design, single 100 mg doses of itraconazole as a polyethylene glycol capsule, with or without a full meal. The same 6 volunteers also received 50 mg or 200 mg with a full meal in a crossover design. In this study, only itraconazole plasma concentrations were measured. The respective pharmacokinetic parameters for itraconazole are presented in the table /provided/.
Table: Oral Bioavailability of Itraconazole (Itraconazole capsules): [Table#7579]

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Metabolism / Metabolites
Itraconazole is extensively metabolized in the liver. In vitro studies have shown that CYP3A4 is the major enzyme involved in the metabolism of itraconazole. While itraconazole can be metabolized to more than 30 metabolites, the main metabolite is hydroxyitraconazole. Hydroxyitraconazole has in vitro antifungal activity comparable to itraconazole; trough plasma concentrations of this metabolite are about twice those of the parent compound. Other metabolites include keto-itraconazole and N-dealkyl-itraconazole.
Itraconazole is metabolized predominantly by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing.
Itraconazole (ITZ) is metabolized in vitro to three inhibitory metabolites: hydroxy-itraconazole (OH-ITZ), keto-itraconazole (keto-ITZ), and N-desalkyl-itraconazole (ND-ITZ). The goal of this study was to determine the contribution of these metabolites to drug-drug interactions caused by ITZ. Six healthy volunteers received 100 mg ITZ orally for 7 days, and pharmacokinetic analysis was conducted at days 1 and 7 of the study. The extent of CYP3A4 inhibition by ITZ and its metabolites was predicted using this data. ITZ, OH-ITZ, keto-ITZ, and ND-ITZ were detected in plasma samples of all volunteers. A 3.9-fold decrease in the hepatic intrinsic clearance of a CYP3A4 substrate was predicted using the average unbound steady-state concentrations (C(ss,ave,u)) and liver microsomal inhibition constants for ITZ, OH-ITZ, keto-ITZ, and ND-ITZ. Accounting for circulating metabolites of ITZ significantly improved the in vitro to in vivo extrapolation of CYP3A4 inhibition compared to a consideration of ITZ exposure alone.

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Biological Half-Life
The terminal half-life of itraconazole generally ranges from 16 to 28 hours after a single dose and increases to 34 to 42 hours with repeated dosing. The metabolite of itraconazole is excreted from the plasma more rapidly than the parent compound.

Hepatotoxicity
Transient, mild-to-moderate elevations in serum aminotransferase levels occur in 1% to 5% of patients on itraconazole. These elevations are largely asymptomatic and self-limited, resolving even with continuation of therapy. Clinically apparent hepatotoxicity is rare but has been well described and can be severe and even fatal. The liver injury from itraconazole typically presents 1 to 6 months after starting therapy with symptoms of fatigue and jaundice. The pattern of serum enzyme elevations is typically cholestatic (Case 1), but cases of severe hepatitis with acute liver failure typically have a hepatocellular enzyme pattern (Case 2). Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. Recovery upon stopping therapy can be delayed for several weeks and generally takes 4 to 10 weeks, although in some cases recovery may be prolonged.
Likelihood score: B (likely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of itraconazole during breastfeeding. However, limited data indicate that maternal itraconazole produces levels in milk that are less than the 5 mg/kg daily doses that have been recommended to treat infants. Until more data become available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. If itraconazole is used during breastfeeding, monitoring of the infant’s liver enzymes should be considered, especially with long courses of therapy.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Most of the itraconazole in plasma is bound to protein (99.8%), with albumin being the main binding component (99.6% for the hydroxy-metabolite). It also has a marked affinity for lipids. Only 0.2% of the itraconazole in plasma is present as the free drug.

[1]. Ultra-performance liquid chromatography electrospray ionization-tandem mass spectrometry method for the simultaneous determination of itraconazole and hydroxy itraconazole in human plasma. J Pharm Anal. 2014 Oct;4(5):316-324.

2-butan-2-yl-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-1,2,4-triazol-3-one is a member of piperazines.
Itraconazole is an antifungal prescription medicine approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain fungal infections, such as:
Histoplasmosis
Certain types of mucocutaneouscandidiasis, including esophageal candidiasis (infection of the esophagus) and oropharyngeal candidiasis (infection of part of the throat)
Histoplasmosis and mucocutaneous candidiasis can be opportunistic infections (OIs) of HIV.
First synthesized in the early 1980s, itraconazole is a broad-spectrum triazole antifungal agent used to treat a variety of infections. It is a 1:1:1:1 racemic mixture of four diastereomers, made up of two enantiomeric pairs, each possessing three chiral centers. Itraconazole was first approved in the US in 1992 and is available orally. While the intravenous formulation of the drug was formerly available, it was discontinued in the US in 2007.
Itraconazole is a orally administered, triazole antifungal agent used in the treatment of systemic and superficial fungal infections. Itraconazole therapy is associated with transient, mild-to-moderate serum elevations and can lead to clinically apparent acute drug induced liver injury.
Itrizole has been reported in Aspergillus fumigatus with data available.
Itraconazole is a synthetic triazole agent with antimycotic properties. Formulated for both topical and systemic use, itraconazole preferentially inhibits fungal cytochrome P450 enzymes, resulting in a decrease in fungal ergosterol synthesis. Because of its low toxicity profile, this agent can be used for long-term maintenance treatment of chronic fungal infections. (NCI04)
A triazole antifungal agent that inhibits cytochrome P-450-dependent enzymes required for ERGOSTEROL synthesis.
See also: Itraconazole (annotation moved to).

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Drug Indication
Itraconazole is indicated for the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: - Blastomycosis, pulmonary and extrapulmonary - Histoplasmosis, including chronic cavitary pulmonary disease and disseminated, nonmeningeal histoplasmosis, and - Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy It is also indicated for the treatment of the following fungal infections in non-immunocompromised patients: - Onychomycosis of the toenail, with or without fingernail involvement, due to dermatophytes (tinea unguium) - Onychomycosis of the fingernail due to dermatophytes (tinea unguium). Itraconazole oral solution is indicated for the treatment of oropharyngeal and esophageal candidiasis.
For the treatment of aspergillosis and candidiasis in companion birds,

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Mechanism of Action
Itraconazole mediates its antifungal activity by inhibiting 14α-demethylase, a fungal cytochrome P450 enzyme that converts lanosterol to ergosterol, a vital component of fungal cell membranes. The azole nitrogen atoms in the chemical structure of itraconazole form a complex with the active site, or the haem iron, of the fungal enzyme to impede its function. The accumulation of lanosterol and 14-methylated sterols results in increased permeability of the fungal cell membrane, and modified membrane-bound enzyme activity, and dysregulated chitin synthesis. Other proposed mechanisms of action of itraconazole include the inhibition of fungal cytochrome c oxidative and peroxidative enzymes that also lead to the disruption of fungal cell membranes.
In vitro studies have demonstrated that itraconazole inhibits the cytochrome P450-dependent synthesis of ergosterol, which is a vital component of fungal cell membranes.

C35H35D3CL2N8O4

708.65

707.258

1217512-35-0

Itraconazole;84625-61-6

3793

White to off-white solid powder

168-170
166.2 °C

5.707

0

9

11

49

1120

0

VHVPQPYKVGDNFY-UHFFFAOYSA-N

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

2-butan-2-yl-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)