Lütjohann D, Marinova M, Schneider B, Oldenburg J, von Bergmann K, Bieber T, Björkhem I, Diczfalusy U
Institute of Clinical Chemistry and Pharmacology, University Clinic, Bonn, Germany.
Int J Clin Pharmacol Ther. 2009 Dec;47(12):709-15. doi: 10.5414/cpp47709.
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.
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.
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.
In conclusion, 4beta-hydroxycholesterol appears to be a sensitive endogenous surrogate marker in human serum for inhibition of CYP3A4 by itraconazole.
伊曲康唑是一种三唑类抗真菌药物，已被证明可作为配体诱导的孕烷X受体介导的CYP3A4基因转录调控的抑制剂。在此，我们研究伊曲康唑治疗期间CYP3A4活性的潜在内源性血清标志物4β-羟基胆固醇。
在一项开放的前瞻性探索性试验中，8名甲癣男性患者接受了两个为期1周的疗程，每日一次服用400mg伊曲康唑。在每个疗程开始和结束时采集空腹血清样本。使用气相色谱-火焰离子化检测法测量胆固醇水平，同时通过气相色谱-质谱法定量胆固醇和胆汁酸前体。
伊曲康唑治疗期间总胆固醇下降了10%（p<0.0005）。胆固醇前体羊毛甾醇和24,25-二氢羊毛甾醇的浓度分别增加了10倍和240倍（两者p均<0.001）。有趣的是，血清羊毛甾醇与胆固醇的比值，即羊毛甾醇下游内源性胆固醇合成的指标，保持不变。在两个疗程中，由CYP3A4介导氧化形成的4β-羟基胆固醇的绝对浓度和经胆固醇校正的浓度均显著下降，平均分别下降29.1%（p=0.0006）和20.8%（p=0.0062）。脑特异性胆固醇代谢产物24S-羟基胆固醇及其与胆固醇的比值分别增加了19.7%（p=0.0422）和34.9%（p=0.0013），而其他胆汁酸前体7α-羟基胆固醇和27-羟基胆固醇的浓度保持不变。
总之，4β-羟基胆固醇似乎是人体血清中伊曲康唑抑制CYP3A4的敏感内源性替代标志物。
