Serum 4β-hydroxycholesterol increases during fluconazole treatment

Purpose The antifungal drugs ketoconazole and itraconazole reduce serum concentrations of 4β-hydroxycholesterol, which is a validated marker for hepatic cytochrome P450 (CYP) 3A4 activity. We tested the effect of another antifungal triazole agent, fluconazole, on serum concentrations of different st...

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Vydáno v:European journal of clinical pharmacology Ročník 77; číslo 5; s. 659 - 669
Hlavní autoři: Lütjohann, Dieter, Stellaard, Frans, Kerksiek, Anja, Lötsch, Jörn, Oertel, Bruno G
Médium: Journal Article
Jazyk:angličtina
Vydáno: Berlin/Heidelberg Springer Berlin Heidelberg 01.05.2021
Springer Nature B.V
Témata:
Antifungal agents
Biomedical and Life Sciences
Biomedicine
Cholesterol
Clinical Trial
Cytochrome P450
Demethylation
Dosage
Fluconazole
Gas chromatography
Hemopoiesis
Itraconazole
Ketoconazole
Lanosterol
Lipid metabolism
Liver
Mass spectroscopy
Pharmacology/Toxicology
Placebos
Sterols
Bile acid precursors
Antifungal
Cholesterol synthesis
Cholesterol metabolism
Cytochrome P450
Oxysterols
ISSN:0031-6970, 1432-1041, 1432-1041
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Shrnutí:Purpose The antifungal drugs ketoconazole and itraconazole reduce serum concentrations of 4β-hydroxycholesterol, which is a validated marker for hepatic cytochrome P450 (CYP) 3A4 activity. We tested the effect of another antifungal triazole agent, fluconazole, on serum concentrations of different sterols and oxysterols within the cholesterol metabolism to see if this inhibitory reaction is a general side effect of azole antifungal agents. Methods In a prospective, double-blind, placebo-controlled, two-way crossover design, we studied 17 healthy subjects (nine men, eight women) who received 400 mg fluconazole or placebo daily for 8 days. On day 1 before treatment and on day 8 after the last dose, fasting blood samples were collected. Serum cholesterol precursors and oxysterols were measured by gas chromatography-mass spectrometry-selected ion monitoring and expressed as the ratio to cholesterol (R_sterol). Results Under fluconazole treatment, serum R_lanosterol and R_24,25-dihydrolanosterol increased significantly without affecting serum cholesterol or metabolic downstream markers of hepatic cholesterol synthesis. Serum R_4β-, R_24S-, and R_27-hydroxycholesterol increased significantly. Conclusion Fluconazole inhibits the 14α-demethylation of lanosterol and 24,25-dihydrolanosterol, regulated by CYP51A1, without reduction of total cholesterol synthesis. The increased serum level of R_4β-hydroxycholesterol under fluconazole treatment is in contrast to the reductions observed under ketoconazole and itraconazole treatments. The question, whether this increase is caused by induction of CYP3A4 or by inhibition of the catabolism of 4β-hydroxycholesterol, must be answered by mechanistic in vitro and in vivo studies comparing effects of various azole antifungal agents on hepatic CYP3A4 activity.
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ISSN:0031-6970
1432-1041
1432-1041
DOI:10.1007/s00228-020-03041-5