Abstract

Objective: Itraconazole, a triazole antifungal agent, has been demonstrated to act as an inhibitor of the ligand induced pregnane X receptor-mediated transcriptional regulation of the CYP3A4 gene. Here, we study the potential endogenous serum marker of CYP3A4 activity, 4beta-hydroxycholesterol, during therapy with itraconazole. Patients and methods: 8 male patients with onychomycosis received two 1-week cycles of treatment with 400 mg itraconazole once daily in an open, prospective exploratory trial. Fasting serum samples were taken at the beginning and at the end of each cycle. The levels of cholesterol were measured using gas chromatography-flame ionization detection, while cholesterol and bile acid precursors were quantified by gas chromatography-mass spectrometry. Results: Total cholesterol decreased by 10% (p < 0.0005) during the itraconazole treatment. Concentrations of the cholesterol precursor lanosterol and 24, 25-dihydrolanosterol increased 10- and 240-fold, respectively (p < 0.001 for both). Interestingly, the ratio of serum lathosterol to cholesterol, an indicator of endogenous cholesterol synthesis downstream from lanosterol, remained unchanged. Absolute and cholesterol-corrected concentrations of 4beta-hydroxycholesterol, formed by CYP3A4-mediated oxidation, decreased significantly during both cycles, on average by 29.1% (p = 0.0006) and 20.8% (p = 0.0062), respectively. The brain-specific cholesterol metabolite 24S-hydroxycholesterol as well as its ratio to cholesterol increased by 19.7% (p = 0.0422) and 34.9% (p = 0.0013), respectively, while the concentrations of the other bile acid precursors, 7alpha-hydroxycholesterol and 27-hydroxycholesterol, remained unchanged. Conclusions: In conclusion, 4beta-hydroxycholesterol appears to be a sensitive endogenous surrogate marker in human serum for inhibition of CYP3A4 by itraconazole.

Author Details

Authors

• D. Lütjohann¹*
• M. Marinova¹
• ²*
• B. Schneider³
• J. Oldenburg²
• K. von Bergmann⁴
• T. Bieber⁵
• I. Björkhem⁶
• U. Diczfalusy⁶

Departments

• ¹ Institute of Clinical Chemistry and Pharmacology,
• ² Institute of Experimental Hematology and Transfusion Medicine,
• ³ Department of Hematology and Oncology,
• ⁴ Department of Clinical Pharmacology,
• ⁵ Department of Dermatology, University Clinic, Bonn, Germany, and
• ⁶ Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Huddinge, Sweden

Address

Prof. Dr. Dr. D. Lütjohann
Institute of Clinical Chemistry and Pharmacology
University Clinic Bonn
Sigmund-Freud-Str. 25
53105 Bonn, Germany
Email: [email protected]

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