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].

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].

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.

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]

---

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.
Itraconazole is extensively metabolized by the liver into a large number of metabolites, including hydroxyitraconazole, the major metabolite. The main metabolic pathways are oxidative scission of the dioxolane ring, aliphatic oxidation at the 1-methylpropyl substituent, N-dealkylation of this 1-methylpropyl substituent, oxidative degradation of the piperazine ring and triazolone scission.
Route of Elimination: Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4) in the liver, resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose.
Half Life: 21 hours

---

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.

Toxicity Summary
Itraconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis 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/or phospholipid biosynthesis.

---

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).

---

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.

---

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.

---

Toxicity Data
No significant lethality was observed when itraconazole was administered orally to mice and rats at dosage levels of 320 mg/kg or to dogs at 200 mg/kg.

---

Interactions
The class IA antiarrhythmic quinidine and class III antiarrhythmic dofetilide are known to prolong the QT interval. Co-administration of quinidine or dofetilide with itraconazole may increase plasma concentrations of quinidine or dofetilide which could result in serious cardiovascular events. Therefore, concomitant administration of itraconazole and quinidine or dofetilide is contraindicated. The class IA antiarrhythmic disopyramide has the potential to increase the QT interval at high plasma concentrations. Caution is advised when itraconazole and disopyramide are administered concomitantly. Concomitant administration of digoxin and itraconazole has led to increased plasma concentrations of digoxin.
Reduced plasma concentrations of itraconazole were reported when itraconazole was administered concomitantly with phenytoin. Carbamazepine, phenobarbital and phenytoin are all inducers of CYP3A4. Although interactions with carbamazepine and phenobarbital have not been studied, concomitant administration of itraconazole and these drugs would be expected to result in decreased plasma concentrations of itraconazole.
Drug interaction studies have demonstrated that plasma concentrations of azole antifungal agents and their metabolites, including itraconazole and hydroxyitraconazole, were significantly decreased when these agents were given concomitantly with rifabutin or rifampin. In vivo data suggest that rifabutin is metabolized in part by CYP3A4. Itraconazole may inhibit the metabolism of rifabutin.
Itraconazole may inhibit the metabolism of busulfan, docetaxel and vinca alkaloids.
For more Interactions (Complete) data for Itraconazole (29 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Rat oral >320 mg/kg
LD50 Mouse oral >320 mg/kg
LD50 Dog oral >200 mg/kg
LD50 Guinea pig oral >160 mg/kg

[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 Agents; Antiprotozoal Agents
Itraconazole capsules are 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, non-meningeal histoplasmosis and Aspergillosis, pulmonary and extrapulmonary, in patients who are intolerant of or who are refractory to amphotericin B therapy. /Included in US product label/
Itraconazole capsules are 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) and Onychomycosis of the fingernail due to dermatophytes (tinea unguium). /Included in US product label/

---

Drug Warnings
/BOXED WARNING/ Congestive Heart Failure, Cardiac Effects: Itraconazole capsules should not be administered for the treatment of onychomycosis in patients with evidence of ventricular dysfunction such as congestive heart failure (CHF) or a history of CHF. If signs or symptoms of congestive heart failure occur during administration of itraconazole capsules, discontinue administration. When itraconazole was administered intravenously to dogs and healthy human volunteers, negative inotropic effects were seen.
/BOXED WARNING/ Drug Interactions: Coadministration of the following drugs are contraindicated with itraconazole capsules: methadone, disopyramide, dofetilide, dronedarone, quinidine, ergot alkaloids (such as dihydroergotamine, ergometrine (ergonovine), ergotamine, methylergometrine (methylergonovine)), irinotecan, lurasidone, oral midazolam, pimozide, triazolam, felodipine, nisoldipine, ranolazine, eplerenone, cisapride, lovastatin, simvastatin and, in subjects with renal or hepatic impairment, colchicine. Coadministration with itraconazole can cause elevated plasma concentrations of these drugs and may increase or prolong both the pharmacologic effects and/or adverse reactions to these drugs. For example, increased plasma concentrations of some of these drugs can lead to QT prolongation and ventricular tachyarrhythmias including occurrences of torsades de pointes, a potentially fatal arrhythmia.
Itraconazole is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation. Although information concerning cross-sensitivity between itraconazole and other triazole or imidazole antifungal agents is not available, the manufacturer states that itraconazole should be used with caution in individuals hypersensitive to other azoles.
Adverse GI effects have been reported in about 1-11% of patients receiving IV or oral itraconazole for the treatment of systemic fungal infections or oropharyngeal or esophageal candidiasis or for empiric anti-fungal therapy. These adverse GI effects usually are transient and respond to symptomatic treatment without alteration of itraconazole therapy; however, reduction of dosage or discontinuance of the drug occasionally may be required.
For more Drug Warnings (Complete) data for Itraconazole (27 total), please visit the HSDB record page.

---

Pharmacodynamics
Itraconazole is an antifungal agent that inhibits cell growth and promotes cell death of fungi. It exhibits in vitro activity against _Blastomyces dermatitidis_, _Histoplasma capsulatum_, _Histoplasma duboisii_, _Aspergillus flavus_, _Aspergillus fumigatus_, and _Trichophyton_ species.

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.

---

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.

---

View More

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

---

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.

---

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