Absorption, Distribution and Excretion
Itraconazole is rapidly absorbed after oral administration. In the oral capsule formulation, peak plasma concentrations of itraconazole are reached within 2 to 5 hours. The observed absolute oral bioavailability of itraconazole is approximately 55%. At the same dose, the exposure to itraconazole in the capsule formulation is lower than that in the oral solution formulation. Maximum absorption is achieved in the presence of sufficient gastric acid. Due to nonlinear pharmacokinetics, itraconazole accumulates in plasma after multiple doses. Steady-state plasma concentrations are typically reached over approximately 15 days, with peak plasma concentrations (Cmax) of 0.5 μg/mL, 1.1 μg/mL, and 2.0 μg/mL after once-daily oral administration of 100 mg, once-daily oral administration of 200 mg, and twice-daily oral administration of 200 mg, respectively. Within one week after oral administration of the solution, itraconazole is primarily excreted as inactive metabolites in the urine (35%) and feces (54%). Following intravenous injection, less than 1% of itraconazole and its active metabolite, hydroxyitraconazole, are excreted by the kidneys. Based on the oral radiolabeled dose, fecal excretion of the parent drug ranges from 3% to 18% of the dose. Since redistribution of itraconazole from keratinocytes appears negligible, clearance from these tissues is associated with epidermal regeneration. Unlike plasma concentrations, drug concentrations in the skin can persist for 2 to 4 weeks after the completion of a 4-week treatment course; in nail keratin (where itraconazole can be detected as early as 1 week after the start of treatment), drug concentrations can persist for at least 6 months after the completion of a 3-month treatment course. The adult volume of distribution exceeds 700 liters. Itraconazole is lipophilic and widely distributed in tissues. Drug concentrations in the lungs, kidneys, liver, bones, stomach, spleen, and muscles are 2 to 3 times higher than the corresponding plasma concentrations, while absorption in keratinocytes (especially the skin) can be up to 4 times higher than plasma concentrations. Drug concentrations in cerebrospinal fluid are significantly lower than plasma concentrations. The mean total plasma clearance after intravenous administration is 278 mL/min. Due to hepatic metabolic saturation, itraconazole clearance decreases at high doses. A randomized crossover study enrolled six healthy male volunteers to investigate the pharmacokinetics of intravenously administered itraconazole and its absolute bioavailability as an oral solution. The observed absolute oral bioavailability of itraconazole was 55%. Itraconazole capsules exhibit the highest oral bioavailability when taken with a meal. A crossover study enrolled six healthy male volunteers who received a single 100 mg dose of itraconazole polyethylene glycol capsules before or after a meal to investigate the pharmacokinetics of itraconazole. These six volunteers also received 50 mg or 200 mg of itraconazole before or after a meal in a crossover design. Only plasma concentrations of itraconazole were measured in this study. The corresponding pharmacokinetic parameters for itraconazole are shown in the table below (provided).
Table: Oral Bioavailability of Itraconazole (Itraconazole Capsules): [Table #7579]

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Metabolism/Metabolites
Itraconazole is primarily metabolized in the liver. In vitro studies have shown that CYP3A4 is the main enzyme involved in the metabolism of itraconazole. Itraconazole can be metabolized into more than 30 metabolites, with hydroxyitraconazole being the major metabolite. The in vitro antifungal activity of hydroxyitraconazole is comparable to that of itraconazole; the plasma trough concentration of this metabolite is approximately twice that of the parent compound. Other metabolites include ketoitraconazole and N-desalkylitraconazole.
Itraconazole is primarily metabolized via the cytochrome P450 3A4 isoenzyme system (CYP3A4), generating various metabolites, with hydroxyitraconazole being the major metabolite. Pharmacokinetic studies indicate that the metabolism of itraconazole may reach saturation after repeated administration. Itraconazole (ITZ) is metabolized in vitro into three inhibitory metabolites: hydroxyitraconazole (OH-ITZ), ketoitraconazole (keto-ITZ), and N-desylitraconazole (ND-ITZ). This study aimed to determine the effects of these metabolites on drug interactions induced by ITZ. Six healthy volunteers received 100 mg of itraconazole (ITZ) orally for seven consecutive days, and pharmacokinetic analyses were performed on days 1 and 7 of the study. These data were used to predict the degree of CYP3A4 inhibition by ITZ and its metabolites. ITZ, hydroxyitraconazole (OH-ITZ), ketoitraconazole (keto-ITZ), and noritraconazole (ND-ITZ) were detected in plasma samples from all volunteers. Based on the mean free steady-state concentrations (C(ss,ave,u)) of ITZ, OH-ITZ, keto-ITZ, and ND-ITZ, and the hepatic microsomal inhibition constant, a 3.9-fold reduction in the intrinsic hepatic clearance of CYP3A4 substrates was predicted. Considering itraconazole circulating metabolites significantly improves the accuracy of inferring CYP3A4 inhibition from in vitro to in vivo compared to considering only itraconazole exposure.

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Biological Half-Life
The terminal half-life of itraconazole after a single dose is typically 16 to 28 hours, which can be prolonged to 34 to 42 hours with repeated dosing. Itraconazole metabolites are excreted from plasma more rapidly than the parent compound.

Hepatotoxicity
In patients taking itraconazole, 1% to 5% experience transient, mild to moderate elevations in serum transaminase levels. These elevations are mostly asymptomatic and resolve spontaneously, returning to normal with continued treatment. Clinically significant hepatotoxicity, while rare, is described in detail and can be severe or even fatal. Itraconazole-induced liver injury typically appears 1 to 6 months after the start of treatment, with symptoms including fatigue and jaundice. The pattern of serum enzyme elevation is usually cholestatic (Case 1), but severe hepatitis cases with acute liver failure often present with hepatocellular enzyme elevations (Case 2). Immune allergic reactions (rash, fever, eosinophilia) and autoantibody formation are uncommon. Recovery after discontinuation of treatment may take several weeks, typically 4 to 10 weeks, but may be prolonged in some cases. Probability score: B (likely to cause clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on the clinical use of itraconazole during lactation. However, limited data suggest that after mothers take itraconazole, the concentration of the drug in breast milk is lower than the recommended daily dose of 5 mg/kg for infant treatment. Until more data are available, it is recommended to prioritize other medications, especially when breastfeeding newborns or preterm infants. If itraconazole is used during lactation, monitoring of the infant's liver enzymes should be considered, especially in cases of long-term treatment.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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Protein binding
Most of itraconazole in plasma is bound to proteins (99.8%), with albumin being the major binding component (99.6% binding to hydroxy metabolites). It also has a significant affinity for lipids. Only 0.2% of itraconazole exists in plasma as a 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-But-2-yl-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-1,2,4-triazol-3-one belongs to the piperazine class of compounds. Itraconazole is a prescription antifungal drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of certain fungal infections, such as: histoplasmosis; certain types of mucocutaneous candidiasis, including esophageal candidiasis (esophageal infection) and oropharyngeal candidiasis (partial throat infection). Histoplasmosis and mucocutaneous candidiasis may be opportunistic infections (OIs), such as HIV. Itraconazole was first synthesized in the early 1980s and is a broad-spectrum triazole antifungal drug used to treat a variety of infections. It is a 1:1:1:1 racemic mixture of four diastereomers, consisting of two pairs of enantiomers, each with three chiral centers. Itraconazole was first approved in the United States in 1992 for oral administration. Although an intravenous formulation was once available, it was discontinued in the United States in 2007. Itraconazole is an oral triazole antifungal drug used to treat systemic and superficial fungal infections. Itraconazole treatment can cause transient, mild to moderate increases in serum concentrations and may lead to clinically significant acute drug-induced liver injury. There are reports and data regarding its effectiveness against Aspergillus fumigatus. Itraconazole is a synthetic triazole drug with antifungal properties. Ittraconazole can be administered topically and systemically, preferentially inhibiting fungal cytochrome P450 enzymes, thereby reducing fungal ergosterol synthesis. Due to its low toxicity, it can be used for long-term maintenance therapy of chronic fungal infections. (NCI04)
A triazole antifungal drug that inhibits the cytochrome P-450-dependent enzyme required for ergosterol synthesis.
See also: itraconazole (note moved to).

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Drug Indications
Itraconazole is indicated for the treatment of the following fungal infections in immunocompromised and non-immune-compromised patients: - Pulmonary blastomycosis and extrapulmonary blastomycosis; - Histoplasmosis, including chronic cavitary lung disease and disseminated non-meningeal histoplasmosis; and - Pulmonary aspergillosis and extrapulmonary aspergillosis, in patients who are intolerant to or unresponsive to amphotericin B. Itraconazole is also indicated for the treatment of the following fungal infections in non-immune-compromised patients: - Onychomycosis of the toenails caused by dermatophytes, with or without nail involvement. (Onychomycosis) - Nail fungal infections caused by dermatophytes (onychomycosis). Itraconazole oral solution is indicated for the treatment of oropharyngeal and esophageal candidiasis.
Used to treat aspergillosis and candidiasis in companion birds,

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Mechanism of Action
Itraconazole exerts its antifungal activity by inhibiting 14α-demethylase, a fungal cytochrome P450 enzyme that converts lanosterol to ergosterol, an essential component of the fungal cell membrane. The azole nitrogen atom in itraconazole's chemical structure forms a complex with the active site of the fungal enzyme (i.e., heme iron), thereby inhibiting its function. The accumulation of lanosterol and 14-methylsterol leads to increased fungal cell membrane permeability, altered membrane-bound enzyme activity, and dysregulation of chitin synthesis. Other mechanisms of action of itraconazole include inhibition of fungal cytochrome c oxidase and peroxidase, resulting in fungal cell membrane disruption. In vitro studies have shown that itraconazole inhibits cytochrome P450-dependent ergosterol synthesis, and ergosterol is an essential component of the fungal cell membrane.

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.)