From the Guidelines
Ketoconazole works by blocking multiple adrenal enzymes, including those involved early in the steroid biosynthetic pathway, which avoids excess circulation of androgen and mineralocorticoid precursors. This mechanism of action is crucial in understanding its effects on the body, particularly in the context of treating conditions like Cushing's syndrome. According to a recent study published in The Lancet Diabetes and Endocrinology 1, ketoconazole's ability to block these enzymes leads to a decrease in gonadal steroid synthesis, which can result in hypogonadism and gynecomastia in men.
The study also highlights the importance of monitoring liver function tests (LFTs) in patients taking ketoconazole, as hepatotoxicity is a potential side effect, seen in 10-20% of patients 1. Despite this, ketoconazole has been shown to be effective in normalizing UFC levels in patients with Cushing's syndrome, with a median response rate of 64.3% 1.
In terms of its antifungal properties, ketoconazole works by inhibiting the synthesis of ergosterol, an essential component of fungal cell membranes. However, this is not the primary mechanism of action relevant to the question of its MOA in the context of treating conditions like Cushing's syndrome.
Key points to consider when using ketoconazole include:
- Its ability to block multiple adrenal enzymes, leading to a decrease in gonadal steroid synthesis
- The potential for hepatotoxicity, which requires regular monitoring of LFTs
- Its effectiveness in normalizing UFC levels in patients with Cushing's syndrome
- The importance of careful review of the patient's medication list for potentially problematic interactions 1.
From the FDA Drug Label
Ketoconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. The mechanism of action (MOA) of ketoconazole is the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase, which blocks the synthesis of ergosterol, a key component of the fungal cell membrane, resulting in the accumulation of methylated sterol precursors and a depletion of ergosterol within the cell membrane, thus weakening the structure and function of the fungal cell membrane 2.
- The key points of the MOA are:
- Inhibition of lanosterol 14α-demethylase
- Blockage of ergosterol synthesis
- Accumulation of methylated sterol precursors
- Depletion of ergosterol in the fungal cell membrane
From the Research
Mode of Action of Ketoconazole
The mode of action of ketoconazole is through the inhibition of sterol-14 alpha-demethylase, a cytochrome P450 (CYP51, Erg11p) enzyme [ 3 ]. This enzyme is involved in the ergosterol biosynthetic pathway, which is essential for fungal cell membrane integrity.
Inhibition of Sterol 14α-Demethylase
Ketoconazole, along with other azole antifungal drugs, acts by inhibiting the cytochrome P450-dependent enzyme sterol 14α-demethylase [ 4 ]. This inhibition leads to a depletion of ergosterol and an accumulation of 14 alpha-methyl-ergosta-8,24(28)-dien-3beta-6 alpha-diol, ultimately disrupting fungal cell membrane function.
Applications of Ketoconazole
Ketoconazole has been explored for its potential use in treating various fungal and protozoan infections, including:
- Fungal infections: Ketoconazole is used as an antifungal agent to treat infections caused by yeasts and filamentous fungi [ 3 ].
- Leishmaniasis: Azole antifungals, including ketoconazole, have been repurposed for the treatment of human leishmaniasis [ 4 ].
- Chagas disease: Ketoconazole has been investigated as a potential treatment for Chagas disease, caused by the protozoan pathogen Trypanosoma cruzi [ 5 ].
Targeting Lanosterol 14α-Demethylase
The cytochrome P450 enzyme lanosterol 14α-demethylase (LDM) is the target of azole antifungals, including ketoconazole [ 6 ]. Understanding the structure and function of this enzyme is crucial for the design of next-generation antifungals that can effectively target LDM and avoid resistance mechanisms.