TY  - JOUR
A1  - Lütjohann, Dieter
A1  - Stellaard, Frans
A1  - Kerksiek, Anja
A1  - Lötsch, Jörn
A1  - Oertel, Bruno Georg
T1  - Serum 4β-hydroxycholesterol increases during fluconazole treatment
T2  - European Journal of Clinical Pharmacology
N2  - 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.
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75578
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-755781
SN  - 1432-1041
VL  - 77
IS  - 5
SP  - 659
EP  - 669
PB  - Springer
CY  - Berlin ; Heidelberg ; New York
ER  -