Itraconazole
Clinical Particulars
Itraconazole (ITZ) is an azole (triazole), fungistatic, antifungal drug and a potent P-glycoprotein and CYP3A4 inhibitor.
Pharmacokinetics
Mechanism of Action
Itraconazole inhibits cytochrome P450-dependent ergosterol synthesis, a vital component of fungal cell membranes (Plumb, 2024; PubChem, 2024).
Other proposed mechanisms include inhibiting fungal cytochrome oxidative and peroxidative enzymes and disrupting fungal cell membranes (Plumb, 2024; PubChem, 2024).
Common Therapeutic Uses
Itraconazole is an antifungal drug used to treat various fungal infections in humans and animals, including aspergillosis, blastomycosis, candidiasis, chromoblastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, and sporotrichosis (Papich, 2011; Plumb, 2024; PubChem, 2024).
Veterinary Applications
Itraconazole is active against dermatophytes and systemic fungi, such as Blastomyces, Histoplasma, and Coccidioides (Papich, 2011; Plumb, 2024; PubChem, 2024).
Pharmacodynamics
Metabolism
Itraconazole is extensively metabolised in the liver. In vitro studies have shown that CYP3A4 is the major enzyme involved in its metabolism.
Distribution
Itraconazole is lipophilic and extensively distributed into tissues. Concentrations in the lung, kidney, liver, bone, stomach, spleen and muscle were two to three times higher than corresponding concentrations in plasma, and the uptake into keratinous tissues, skin in particular, was up to four times higher. Concentrations in the cerebrospinal fluid are much lower than in plasma.
Elimination
Faecal 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.
Precautions
Adverse Effects
Cytochrome P450 inhibition: ITZ is a P450 inhibitor and an EC 3.6.3.44 (xenobiotic-transporting ATPase) inhibitor. Cytochrome P450 inhibition is less than ketoconazole but still affects some low-therapeutic index drugs (Papich, 2011)
Hepatotoxicity: Transient, mild-to-moderate elevations in serum aminotransferase levels occur in 1% to 5% of human patients on itraconazole. Similar effects are expected in veterinary patients. In dogs, hepatotoxicity is one of the most common adverse effects (Plumb, 2024; PubChem, 2024).
Availability
Identifiers
Systematic Name: IUPAC Name - (Plumb, 2024; PubChem, 2024).
Formula: C35 H38 Cl2 N8 O4
Pharmacotherapeutic group: Antifungal agents
ATC Code(s): J02AC02 (WHOCC - ATC/DDD Index, 2024)
ATC Vet Code(s): QJ02AC02
Evidence Base
Carpenter, J.W., Harms, C.A. (Eds.), 2023. Carpenter’s Exotic Animal Formulary, Sixth edition. ed. Elsevier, St. Louis, Missouri.
Papich, M.G., 2011. Saunders handbook of veterinary drugs: small and large animal, 3rd ed. ed. Elsevier/Saunders, Philadelphia, PA.
Plumb, D., 2024. Itraconazole [WWW Document]. URL https://app.plumbs.com/drug/yB1yAq7aNTPROD (accessed 8.10.24).