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Itraconazole Bioequivalence Revisited: Influence of Gender on Highly Variable Drugs 伊曲康唑生物等效性重访:性别对高度可变药物的影响

The open drug metabolism journal

Pub Date : 2007-12-18 DOI: 10.2174/1874073100701010007

P. Fagiolino, Nicolás González, M. Vázquez, R. Eiraldi

Highly variable drugs have been defined as drugs with a residual variability of more than 30% in terms of the ANOVA coefficient of variation. Different approaches have been proposed during the last years to deal with this problem but the topic remains controversial. Itraconazole, a highly variable drug, has low bioavailability with a high CYP3A4 presystemic biotransformation. Also, it has a very poor aqueous solubility which is very dependent on the pH of the dissolution medium. The pregnane X receptor (PXR) has been shown to mediate the genomic effects of progesterone and estradiol in the expression of the cytochrome P-450 gene family, which plays an important role in the metabolism of hormones and xenobiotics. During the menstrual cycle both hormone concentrations vary, providing a rationale for the more variable CYP3A4 activity in women. The analysis of the data of an itraconazole bioequivalence study involving 24 healthy volunteers (12 men and 12 women) carried out by other investigators enables us to conclude that women have less oral bioavailability and more variable AUC than men. Low bioavailability seems to be related with the higher stomach pH observed in women and variability with the aforementioned menstrual cycle incidence on both pH and CYP3A4 expression. The lower variability observed in men made it possible to discriminate differences in AUC’s variability displayed by each brand.

高变异性药物被定义为在方差分析系数方面剩余变异性大于30%的药物。在过去的几年里，人们提出了不同的方法来处理这个问题，但这个话题仍然存在争议。伊曲康唑是一种高度可变的药物，具有低生物利用度和高CYP3A4系统前生物转化。此外，它的水溶性很差，这很大程度上取决于溶解介质的pH值。孕激素X受体(PXR)介导孕酮和雌二醇在细胞色素P-450基因家族表达中的基因组效应，该基因家族在激素和外源代谢中起重要作用。在月经周期中，这两种激素的浓度变化，为女性CYP3A4活性的变化提供了一个基本原理。通过对24名健康志愿者(12男12女)参与的伊曲康唑生物等效性研究数据的分析，我们得出结论:女性口服生物利用度比男性低，AUC变化更大。低生物利用度似乎与女性较高的胃pH值以及上述月经周期对pH值和CYP3A4表达的影响有关。在男性中观察到的较低变异性使得区分每个品牌显示的AUC变异性的差异成为可能。

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引用次数: 8

Novel Role of Soluble Epoxide Hydrolase in Regulating Cholesterol in Mammalian Cells. 可溶性环氧化物水解酶在调节哺乳动物细胞胆固醇中的新作用。

The open drug metabolism journal

Pub Date : 2007-01-01 DOI: 10.2174/1874073100701010001

Ahmed Enayetallah, Li Cao, David F Grant

Soluble epoxide hydrolase (sEH) is becoming an attractive therapeutic target in cardiovascular disease. Recently, known human sEH polymorphisms were associated with elevated plasma cholesterol and atherosclerosis. In this study we evaluated the potential role of sEH in regulating cholesterol metabolism through modulating the levels of fatty acid epoxide substrates and/or their corresponding diol products known to activate peroxisome proliferator activated receptors (PPARs). We measured changes in cholesterol levels induced by expressing sEH proteins in mammalian cell lines and in response to treatment with various sEH-related compounds. Our results indicate that sEH has a cholesterol lowering effect that is mediated at least in part through its C-terminal hydrolase activity. In addition, several fatty acid epoxides and their corresponding diols showed cholesterol lowering effects in the current study. In conclusion, this study provides evidence that fatty acid epoxides and diols are endogenous cholesterol lowering molecules and that sEH may be involved in cholesterol regulation by modulating their levels.

可溶性环氧化物水解酶(sEH)正成为心血管疾病治疗中一个有吸引力的靶点。最近，已知的人类sEH多态性与血浆胆固醇升高和动脉粥样硬化有关。在这项研究中，我们评估了sEH通过调节脂肪酸环氧化物底物和/或其相应的二醇产物的水平来调节胆固醇代谢的潜在作用，这些产物已知可以激活过氧化物酶体增殖物激活受体(PPARs)。我们测量了在哺乳动物细胞系中表达sEH蛋白引起的胆固醇水平变化，以及对各种sEH相关化合物处理的反应。我们的研究结果表明，sEH具有降低胆固醇的作用，至少部分是通过其c端水解酶活性介导的。此外，几种脂肪酸环氧化物及其相应的二醇在本研究中显示出降低胆固醇的作用。总之，本研究提供了证据，证明脂肪酸环氧化物和二醇是内源性降胆固醇分子，sEH可能通过调节其水平参与胆固醇调节。

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引用次数: 12

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