Serum 4β-hydroxycholesterol increases during fluconazole treatment.

Area of Science:

• Biochemistry
• Pharmacology
• Metabolism

Background:

• Azole antifungal agents can affect cholesterol metabolism.
• Ketoconazole and itraconazole reduce serum 4β-hydroxycholesterol, a marker for hepatic cytochrome P450 (CYP) 3A4 activity.
• The effect of fluconazole on sterols and oxysterols is not well understood.

Purpose of the Study:

• To investigate the effect of fluconazole on serum sterols and oxysterols in cholesterol metabolism.
• To determine if the observed changes are a general side effect of azole antifungal agents.

Main Methods:

• Prospective, double-blind, placebo-controlled, two-way crossover study with 17 healthy subjects.
• Subjects received 400 mg fluconazole or placebo daily for 8 days.
• Serum sterols and oxysterols were measured by gas chromatography-mass spectrometry-selected ion monitoring.

Main Results:

• Fluconazole significantly increased serum R_lanosterol and R_24,25-dihydrolanosterol.
• Serum cholesterol and downstream markers of hepatic cholesterol synthesis remained unaffected.
• Serum R_4β-, R_24S-, and R_27-hydroxycholesterol levels increased significantly.

Conclusions:

• Fluconazole inhibits lanosterol 14α-demethylation (CYP51A1) without reducing overall cholesterol synthesis.
• Increased R_4β-hydroxycholesterol under fluconazole differs from ketoconazole and itraconazole effects.
• Further studies are needed to elucidate the mechanism behind increased R_4β-hydroxycholesterol and fluconazole's impact on CYP3A4 activity.