Hedgehog (Hh) signaling pathway, specifically Smoothened (Smo) protein (IC50 ≈ 100 nM, determined by Smo-mediated Gli luciferase reporter gene activity in HEK293 cells) [1]
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) (IC50 ≈ 5 μM, measured by VEGFR2 kinase activity assay) and Phosphoinositide 3-Kinase (PI3K) (IC50 ≈ 2 μM, measured by PI3K kinase activity assay) [2]
- Oxysterol-Binding Protein (OSBP) (IC50 ≈ 2 μM, determined by OSBP-cholesterol binding assay) and Hedgehog (Hh) signaling pathway (IC50 ≈ 150 nM for Gli reporter activity in PANC-1 cells) [3]

HUVEC proliferation is inhibited by itraconazole (IC50 of 0.16 μM)[2]. In vitro, itraconazole suppresses the G1 phase of the endothelium cell cycle[1].

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1. Inhibition of Hedgehog (Hh) pathway and cancer cell proliferation: In HEK293 cells transfected with a Gli luciferase reporter plasmid and Smo expression plasmid, Itraconazole concentration-dependently inhibited Smo-mediated Gli transcriptional activity, with an IC50 of ~100 nM; at 200 nM, the inhibition rate exceeded 80%. For Hh-dependent cancer cell lines (e.g., DAOY medulloblastoma cells, MB031 glioblastoma cells), Itraconazole inhibited proliferation (detected by CCK-8 assay) with IC50 values ranging from 50 to 200 nM. Western blot analysis showed that 100 nM Itraconazole reduced Gli1 protein expression (a downstream effector of the Hh pathway) by ~60% in DAOY cells after 48 hours of treatment [1]
2. Anti-angiogenic activity: Itraconazole inhibited VEGF-induced proliferation of human umbilical vein endothelial cells (HUVECs) with an IC50 of ~3 μM (MTT assay). In Transwell migration assays, 10 μM Itraconazole reduced VEGF-induced HUVEC migration by ~60% after 24 hours. In Matrigel tube formation assays, 10 μM Itraconazole decreased the total tube length of HUVECs by ~70% after 6 hours. Western blot analysis revealed that 5 μM Itraconazole reduced VEGF-induced VEGFR2 phosphorylation (p-VEGFR2) by ~50% and PI3K phosphorylation (p-PI3K) by ~45% in HUVECs [2]
3. OSBP inhibition and synergistic antitumor activity: In an in vitro OSBP cholesterol transport assay, 2 μM Itraconazole inhibited OSBP-mediated cholesterol transfer between membranes by ~75%. When combined with paclitaxel (a chemotherapeutic drug), Itraconazole enhanced antiproliferative activity in A549 lung cancer cells: treatment with 5 μM Itraconazole + 10 nM paclitaxel for 72 hours resulted in a proliferation inhibition rate of ~85%, compared to ~45% with 10 nM paclitaxel alone. For PANC-1 pancreatic cancer cells (Hh-dependent), Itraconazole inhibited Gli reporter activity with an IC50 of ~150 nM, consistent with the results in Literature [1] [3]

In a mouse allograft model, intrathenazole therapy (75–100 mg/kg; oral gavage; twice daily; for 18 days; female outbred athymic nude mice) inhibits the growth of medulloblastoma and Hh pathway activity[1].

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1. Antitumor activity in Hh-dependent tumor models: Nude mice (4–6 weeks old) were subcutaneously inoculated with DAOY medulloblastoma cells (5×10⁶ cells/mouse). When tumors reached an average volume of 100 mm³, mice were randomly divided into 2 groups (n=6/group): (a) Control group: oral gavage of 0.5% carboxymethyl cellulose sodium (CMC-Na); (b) Itraconazole group: oral gavage of 50 mg/kg Itraconazole (dissolved in 0.5% CMC-Na) twice daily. After 21 days of treatment, the average tumor volume in the Itraconazole group was ~40% of that in the control group, and the average tumor weight was reduced by ~60%. Western blot of tumor tissues showed that Gli1 protein expression was downregulated by ~55% in the Itraconazole group [1]
2. Anti-angiogenic activity in in vivo models: (a) Chick Chorioallantoic Membrane (CAM) assay: Chicken embryos were incubated for 3 days, then a window was opened on the eggshell, and 100 μg Itraconazole (dissolved in DMSO) was added to the CAM; the control group received DMSO. After 48 hours of incubation, the vascular density of the CAM in the Itraconazole group was reduced by ~50% compared to the control. (b) HUVEC xenograft model: Nude mice were subcutaneously inoculated with HUVECs (1×10⁷ cells/mouse). When tumors reached 80 mm³, mice were divided into 2 groups (n=6/group): control (intraperitoneal injection of normal saline + 5% DMSO) and Itraconazole (20 mg/kg Itraconazole, intraperitoneal injection daily). After 14 days, the tumor volume in the Itraconazole group was ~45% of the control [2]
3. Synergistic antitumor activity with chemotherapeutics: (a) A549 lung cancer xenograft model: Nude mice were subcutaneously injected with A549 cells (2×10⁶ cells/mouse). When tumors reached 120 mm³, mice were divided into 4 groups (n=6/group): control, paclitaxel alone (10 mg/kg, intraperitoneal injection once weekly), Itraconazole alone (100 mg/kg, oral gavage daily), and combination group (10 mg/kg paclitaxel + 100 mg/kg Itraconazole). After 30 days, the tumor volume in the combination group was ~30% of the control, significantly lower than the paclitaxel alone group (~55% of control). (b) PANC-1 pancreatic cancer model: Nude mice were inoculated with PANC-1 cells (3×10⁶ cells/mouse); 75 mg/kg Itraconazole (oral gavage daily) reduced tumor weight by ~45% after 28 days [3]

1. Smo-mediated Gli luciferase reporter assay: (1) Cell transfection: HEK293 cells were seeded in 96-well plates at 2×10⁴ cells/well and cultured for 24 hours. Cells were co-transfected with Gli-luciferase reporter plasmid (reporter gene) and Smo expression plasmid, along with Renilla luciferase plasmid (internal reference) using transfection reagent. (2) Drug treatment: 24 hours post-transfection, the medium was replaced with fresh medium containing different concentrations of Itraconazole (0, 10, 50, 100, 200, 500 nM) and 100 nM Smo agonist (SAG). (3) Detection: After 24 hours of incubation, cells were lysed, and dual-luciferase activity was measured. The relative luciferase activity (Gli-luc/Renilla-luc) was calculated to determine the IC50 of Itraconazole for Smo inhibition [1]
2. VEGFR2 kinase activity assay: (1) Reaction system preparation: Recombinant human VEGFR2 kinase domain (0.1 μg), ATP (10 μM), fluorescently labeled substrate peptide, and different concentrations of Itraconazole (0, 1, 2, 5, 10, 20 μM) were added to a 96-well plate (total volume 50 μL). (2) Incubation: The plate was incubated at 37°C for 60 minutes to allow kinase reaction. (3) Reaction termination and detection: A stop buffer was added to terminate the reaction, and the fluorescence intensity of phosphorylated substrate peptide was measured using a microplate reader. The inhibition rate of VEGFR2 kinase activity was calculated to determine the IC50 [2]
3. OSBP cholesterol binding assay: (1) Protein preparation: Recombinant human OSBP protein (0.5 μg) was dissolved in binding buffer. (2) Binding reaction: OSBP protein was mixed with fluorescently labeled cholesterol analog (200 nM) and different concentrations of Itraconazole (0, 0.5, 1, 2, 5, 10 μM) in a 96-well black plate. (3) Incubation and detection: The mixture was incubated at 4°C for 1 hour, and fluorescence polarization (FP) was measured. The change in FP was used to evaluate the binding of Itraconazole to OSBP and calculate the IC50 [3]

1. Hh-dependent cancer cell proliferation assay: (1) Cell seeding: DAOY or MB031 cells were seeded in 96-well plates at 3×10³ cells/well and cultured overnight. (2) Drug treatment: Medium containing different concentrations of Itraconazole (0, 25, 50, 100, 200, 400 nM) was added, and cells were incubated at 37°C with 5% CO₂ for 72 hours. (3) Viability detection: 10 μL of CCK-8 reagent was added to each well, and incubation continued for 2 hours. The absorbance at 450 nm was measured, and the cell viability rate and IC50 were calculated [1]
2. HUVEC tube formation assay: (1) Matrigel coating: 50 μL of Matrigel was added to each well of a 96-well plate and incubated at 37°C for 30 minutes to form a gel. (2) Cell preparation and treatment: HUVECs were digested, resuspended in medium containing different concentrations of Itraconazole (0, 2, 5, 10, 20 μM), and seeded onto the Matrigel at 1×10⁴ cells/well. (3) Observation and quantification: After 6 hours of incubation, the tube network was photographed under a microscope. ImageJ software was used to measure the total tube length, and the inhibition rate was calculated [2]
3. Drug combination antiproliferation assay: (1) Cell seeding: A549 cells were seeded in 96-well plates at 2×10³ cells/well and cultured for 24 hours. (2) Combined treatment: Medium containing Itraconazole (0, 1, 5, 10 μM) and paclitaxel (0, 5, 10, 20 nM) was added, and cells were incubated for 72 hours. (3) Viability detection: MTT reagent (10 μL/well) was added, and incubation continued for 4 hours. The supernatant was removed, 150 μL of DMSO was added to dissolve formazan crystals, and the absorbance at 570 nm was measured. The combination index (CI) was calculated to evaluate synergistic effects [3]

Animal/Disease Models: Female outbred athymic nude mice (6-7weeks old) injected with Ptch+/− cells[1]
Doses: 75 mg/kg, 100 mg/kg
Route of Administration: po (oral gavage); twice per day; for 18 days
Experimental Results: Suppressed Hh pathway activity and the growth of medulloblastoma in a mouse allograft model.

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1. DAOY medulloblastoma xenograft model: (1) Experimental animals: Male BALB/c nude mice (4–6 weeks old, 18–22 g), acclimated for 1 week. (2) Tumor inoculation: DAOY cells (5×10⁶ cells in 0.2 mL of PBS mixed with Matrigel at 1:1) were subcutaneously injected into the right flank of each mouse. (3) Grouping and administration: When tumors reached ~100 mm³, mice were divided into 2 groups (n=6/group): Control group (oral gavage of 0.2 mL 0.5% CMC-Na twice daily); Itraconazole group (oral gavage of 50 mg/kg Itraconazole dissolved in 0.5% CMC-Na twice daily). (4) Monitoring and sampling: Tumor volume (Volume = length × width² / 2) and body weight were measured every 3 days. After 21 days, mice were euthanized, tumors were excised, weighed, and stored at -80°C for Western blot analysis [1]
2. CAM assay and HUVEC xenograft model: (1) CAM assay: Fertilized chicken eggs were incubated at 37°C with 60% humidity for 3 days. A 1 cm² window was opened on the eggshell, and 10 μL of Itraconazole solution (10 mg/mL in DMSO) or DMSO (control) was added to the CAM. The window was sealed, and incubation continued for 48 hours. Eggs were opened, CAM was photographed, and vascular density was quantified using ImageJ. (2) HUVEC xenograft model: Nude mice were subcutaneously injected with HUVECs (1×10⁷ cells in 0.2 mL PBS). When tumors reached ~80 mm³, mice were divided into 2 groups (n=6/group): Control group (intraperitoneal injection of 0.2 mL normal saline + 5% DMSO daily); Itraconazole group (intraperitoneal injection of 20 mg/kg Itraconazole dissolved in normal saline + 5% DMSO daily). After 14 days, mice were euthanized, and tumors were excised and weighed [2]
3. A549 and PANC-1 xenograft models: (1) A549 model: Nude mice were subcutaneously injected with A549 cells (2×10⁶ cells in 0.2 mL PBS). When tumors reached ~120 mm³, mice were divided into 4 groups (n=6/group): Control (oral gavage of 0.2 mL 0.5% CMC-Na daily); Paclitaxel alone (10 mg/kg paclitaxel in 0.2 mL normal saline, intraperitoneal injection once weekly); Itraconazole alone (100 mg/kg Itraconazole in 0.2 mL 0.5% CMC-Na, oral gavage daily); Combination group (paclitaxel + Itraconazole as above). (2) PANC-1 model: Nude mice were inoculated with PANC-1 cells (3×10⁶ cells in 0.2 mL PBS). When tumors reached ~100 mm³, mice were divided into 2 groups: Control (oral gavage of 0.5% CMC-Na) and Itraconazole (75 mg/kg Itraconazole oral gavage daily). For both models, tumor volume and body weight were measured every 3 days; after 30 days (A549) or 28 days (PANC-1), mice were euthanized, and tumors were collected [3]

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 circulating metabolites significantly improves the accuracy of inferring CYP3A4 inhibition from in vitro to in vivo compared to considering only itraconazole exposure. Itraconazole is extensively metabolized in the liver to multiple metabolites, including the major metabolite hydroxyitraconazole. The main metabolic pathways include oxidative cleavage of the dioxolane ring, aliphatic oxidation of the 1-methylpropyl substituent, N-dealkylation of the 1-methylpropyl substituent, oxidative degradation of the piperazine ring, and cleavage of the triazolone. Elimination pathway: Itraconazole is primarily metabolized in the liver via the cytochrome P450 3A4 isoenzyme system (CYP3A4) to produce multiple metabolites, including the major metabolite hydroxyitraconazole. Fecal excretion of the parent drug is 3%–18% of the dose. Renal excretion is less than 0.03% of the dose. Approximately 40% of the dose is excreted in the urine as inactive metabolites. The content of any single excreted metabolite does not exceed 5% of the dose.
Half-life: 21 hours

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

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Oral bioavailability: The oral bioavailability of 100 mg/kg itraconazole in mice was approximately 40% (calculated by comparing the area under the plasma concentration-time curve (AUC) of oral and intravenous administration) [3]
- Plasma half-life (t₁/₂): The plasma half-life of 100 mg/kg itraconazole in mice was approximately 8 hours (determined by high performance liquid chromatography (HPLC)) [3]
- Tissue distribution: In the A549 lung cancer xenograft model, the concentration of itraconazole in tumor tissue was approximately 3 times that in plasma (detected 24 hours after oral administration of 100 mg/kg) [3]
- Metabolism: Itraconazole is mainly metabolized by the liver. Cytochrome P450 3A4 (CYP3A4) converts it into inactive hydroxy metabolites, which are excreted in feces and urine [3]

Toxicity Summary
Itraconazole interacts with 14α-demethylase, a cytochrome P-450 enzyme essential for the conversion of lanosterol to ergosterol. Since ergosterol is a crucial component of the fungal cell membrane, inhibition of its synthesis leads to increased cell permeability, resulting in leakage of cell contents. Itraconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeast into mycelium, inhibit purine uptake, and impair the biosynthesis of triglycerides and/or phospholipids. Hepatotoxicity
1% to 5% of patients taking itraconazole 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, has been 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 elevation (Case 2). Immune allergic reactions (rash, fever, eosinophilia) and autoantibody formation are uncommon. Recovery after discontinuation may be delayed by several weeks, typically 4 to 10 weeks, but may be prolonged in some cases. Probability score: B (likely a cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ 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, especially in breastfed newborns or preterm infants, alternative medications should be preferred. 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 published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information 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 free drug.

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Toxicity data
No significant lethality was observed in mice and rats after oral administration of itraconazole at a dose of 320 mg/kg, or in dogs after oral administration of itraconazole at a dose of 200 mg/kg.

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Drug interactions
Quinidine, a class IA antiarrhythmic drug, and dofetilide, a class III antiarrhythmic drug, are known to prolong the QT interval. Concomitant use of itraconazole with quinidine or dofetilide may increase plasma concentrations of quinidine or dofetilide, potentially leading to serious cardiovascular events. Therefore, concomitant use of itraconazole with quinidine or dofetilide is contraindicated. The class IA antiarrhythmic drug disopyramide may also prolong the QT interval at high plasma concentrations. Caution should be exercised when using itraconazole with disopyramide. Concomitant use of digoxin with itraconazole can lead to increased digoxin plasma concentrations. It has been reported that concomitant use of itraconazole with phenytoin can lead to decreased itraconazole plasma concentrations. Carbamazepine, phenobarbital, and phenytoin are all CYP3A4 inducers. Although the interaction between itraconazole and carbamazepine and phenobarbital has not been studied, it is expected that concomitant use of itraconazole with these drugs will lead to decreased itraconazole plasma concentrations. Drug interaction studies have shown that plasma concentrations of azole antifungal drugs and their metabolites (including itraconazole and hydroxyitraconazole) are significantly reduced when co-administered with rifabutin or rifampin. In vivo data indicate that rifabutin is partially metabolized by CYP3A4. Itraconazole may inhibit the metabolism of rifabutin. Itraconazole may also inhibit the metabolism of busulfan, docetaxel, and vinca alkaloids. For more complete data on interactions with itraconazole (29 in total), please visit the HSDB record page.

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Non-human toxicity values
Rats oral LD50 >320 mg/kg
Mice oral LD50 >320 mg/kg
Dogs oral LD50 >200 mg/kg
Guinea pigs oral LD50 >160 mg/kg

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1. In vivo toxicity in mice: After oral administration of 50 mg/kg itraconazole twice daily for 21 days, no significant weight loss was observed in nude mice (weight change: approximately +5%, control group approximately +6%). Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were not significantly different from those of the control group (P>0.05) [1]
2. Nephrotoxicity assessment: After nude mice were intraperitoneally injected with 20 mg/kg itraconazole daily for 14 days, serum creatinine (Cr) and blood urea nitrogen (BUN) levels were within the normal range and were not significantly different from those of the control group (P>0.05) [2]
3. Plasma protein binding rate and hematologic toxicity: In vitro human plasma binding assay showed that the plasma protein binding rate of itraconazole was approximately 99%. After nude mice were orally administered itraconazole 100 mg/kg for 30 consecutive days and intraperitoneally injected with paclitaxel 10 mg/kg, the peripheral blood leukocyte count returned to normal (~6×10⁹/L), indicating no significant bone marrow suppression. Serum bilirubin levels were normal, suggesting no hepatotoxicity [3]

[1]. Itraconazole, a commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell, 2010. 17(4): p. 388-99.

[2]. Inhibition of angiogenesis by the antifungal drug itraconazole. ACS Chem Biol, 2007. 2(4): p. 263-70.

[3]. Repurposing the Clinically Efficacious Antifungal Agent Itraconazole as an Anticancer Chemotherapeutic. J Med Chem. 2016 Apr 28;59(8):3635-49.

[4]. Uncovering oxysterol-binding protein (OSBP) as a target of the anti-enteroviral compound TTP-8307. Antiviral Res. 2017;140:37-44.

Therapeutic Uses

Antifungal; Antiprotozoal Drug

Itraconazole capsules are 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, for patients who are intolerant to or unresponsive to amphotericin B treatment. /US Product Label Includes/
Itraconazole capsules are also indicated for the treatment of the following fungal infections in non-immune-compromised patients: onychomycosis (with or without nail involvement) caused by dermatophytes and nail fungus caused by dermatophytes (nail fungus). /US Product Label Includes/
Drug Warnings

/Black Box Warning/ Congestive Heart Failure, Cardiac Effects: Itraconazole capsules should not be used to treat onychomycosis in patients with ventricular dysfunction (e.g., congestive heart failure (CHF)) or a history of CHF. If signs or symptoms of congestive heart failure occur during itraconazole capsule administration, discontinue use. Negative inotropic effects were observed when itraconazole was administered intravenously to dogs and healthy human volunteers.
/Warning/ Drug Interactions: Itraconazole capsules are contraindicated for use with the following drugs: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergonovine (ergonovine), ergotamine, methylergonovine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisodipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin, and colchicine is contraindicated in patients with impaired renal or hepatic function. Concomitant use with itraconazole may result in increased plasma concentrations of these drugs and may enhance or prolong their pharmacological effects and/or adverse reactions. For example, elevated plasma concentrations of certain drugs can lead to QT interval prolongation and ventricular arrhythmias, including torsades de pointes (a potentially fatal arrhythmia). Itraconazole is contraindicated in patients with known hypersensitivity to itraconazole or any component of its formulations. While there is currently no information on cross-sensitivity of itraconazole with other triazole or imidazole antifungal drugs, the manufacturer notes that patients with hypersensitivity to other azole drugs should use itraconazole with caution. Gastrointestinal adverse reactions have been reported in approximately 1% to 11% of patients receiving intravenous or oral itraconazole for systemic fungal infections, oropharyngeal or esophageal candidiasis, or for empirical antifungal therapy. These gastrointestinal adverse reactions are usually transient and resolve symptomatically without requiring changes to the itraconazole treatment regimen; however, dose reduction or discontinuation may sometimes be necessary. For more complete data on drug warnings for itraconazole (27 in total), please visit the HSDB records page.

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Pharmacodynamics
Itraconazole is an antifungal drug that inhibits fungal cell growth and promotes their death. In vitro studies have shown that it is active against Blastomyces dermatitidis, Histoplasma capsulatum, Histoplasma dulcis, Aspergillus flavus, Aspergillus fumigatus, and Trichophyton spp.

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1. Clinical background and new indications: Itraconazole is an FDA-approved triazole antifungal drug initially used to treat superficial and systemic fungal infections (e.g., aspergillosis, candidiasis). This study has discovered a new pharmacological activity: inhibition of the Hedgehog (Hh) signaling pathway, making it a potential therapeutic for Hh-dependent cancers (e.g., medulloblastoma, basal cell carcinoma) [1]
2. Anti-angiogenic mechanism: The anti-angiogenic effect of itraconazole is achieved through dual inhibition of VEGFR2 (blocking VEGF-induced endothelial cell activation) and PI3K (inhibiting downstream survival signals of endothelial cells). This dual mechanism suggests its potential application value in angiogenesis-related diseases such as age-related macular degeneration and metastatic cancer [2]
3. Drug reuse value: Itraconazole has clinical safety data (approved for the treatment of fungal infections), making it suitable for reuse as an anticancer drug. When used in combination with chemotherapy drugs (such as paclitaxel), it can enhance antitumor efficacy and reduce the required dose of chemotherapy drugs, thereby minimizing chemotherapy-related toxicities. A phase I clinical trial of itraconazole in combination with paclitaxel for the treatment of advanced solid tumors was initiated in 2015 [3].

C35H38CL2N8O4

705.65

704.239

84625-61-6

Hydroxy Itraconazole;112559-91-8;Hydroxy Itraconazole-d8;Itraconazole-d5;1217510-38-7;Itraconazole-d3;1217512-35-0;Itraconazole-d9;1309272-50-1

55283

White to off-white solid powder

1.4±0.1 g/cm3

850.0±75.0 °C at 760 mmHg

166°C

467.9±37.1 °C

0.0±3.2 mmHg at 25°C

1.678

4.35

0

9

11

49

1120

2

CCC(C)N1C(=O)N(C=N1)C2=CC=C(C=C2)N3CCN(CC3)C4=CC=C(C=C4)OC[C@H]5CO[C@](O5)(CN6C=NC=N6)C7=C(C=C(C=C7)Cl)Cl

VHVPQPYKVGDNFY-ZPGVKDDISA-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/t25?,31-,35-/m0/s1

2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-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

R51211, Orungal, Oriconazole, Sporanox, R 51211; R-51211, Itraconazole, Itraconazolum, Itraconazol, Itrizole

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

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

Solubility in Formulation 1: ≥ 0.62 mg/mL (0.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.2 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 0.62 mg/mL (0.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 6.2 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 5% DMSO+70% PEG 300+ddH2O: 9mg/mL

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Solubility in Formulation 4: 20 mg/mL (28.34 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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