| 4beta-hydroxycholesterol as a marker of CYP3A4 inhibition in vivo - effects of itraconazole in man. | |
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MedLine Citation:
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PMID: 19954708 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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D L?tjohann; M Marinova; B Schneider; J Oldenburg; K von Bergmann; T Bieber; I Bj?rkhem; U Diczfalusy |
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Publication Detail:
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Type: Clinical Trial; Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: International journal of clinical pharmacology and therapeutics Volume: 47 ISSN: 0946-1965 ISO Abbreviation: Int J Clin Pharmacol Ther Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-12-03 Completed Date: 2010-02-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9423309 Medline TA: Int J Clin Pharmacol Ther Country: Germany |
Other Details:
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Languages: eng Pagination: 709-15 Citation Subset: IM |
Affiliation:
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Institute of Clinical Chemistry and Pharmacology, University Clinic, Bonn, Germany. dieter.luetjohann@ukb.uni-bonn.de |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Antifungal Agents
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therapeutic use Biomarkers, Pharmacological / blood* Cholesterol / blood, metabolism Cytochrome P-450 CYP3A / antagonists & inhibitors* Humans Hydroxycholesterols / blood* Itraconazole / therapeutic use Male Onychomycosis / drug therapy |
| Chemical | |
Reg. No./Substance:
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0/Antifungal Agents; 0/Biomarkers, Pharmacological; 0/Hydroxycholesterols; 17320-10-4/cholest-5-ene-3,4-diol; 57-88-5/Cholesterol; 84625-61-6/Itraconazole; EC 1.14.13.67/CYP3A4 protein, human; EC 1.14.14.1/Cytochrome P-450 CYP3A |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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