The erythromycin breath test reflects P-glycoprotein function independently of cytochrome P450 3A activity
The erythromycin breath test reflects P-glycoprotein function independently of cytochrome P450 3A activity
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DOI：
10.1016/j.clpt.2006.06.002
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发表时间：
2006-09-01
影响因子：
6.7
通讯作者：
Wilkinson, Grant R.
中科院分区：
文献类型：
--
作者：
Kurnik, Daniel;Wood, Alastair J. J.;Wilkinson, Grant R.
背景。红霉素呼气试验（ERBT）已被广泛用于个体细胞色素P450 (CYP) 3A活性的表型测量，以及其受抑制剂或诱变剂的调节。然而，这一测量实际反映了什么并不完全清楚，因为除了CYP3A，动物研究表明p -糖蛋白也参与红霉素的肝脏处置。因此，研究旨在确定tariquar（一种不影响CYP3A活性的强效p糖蛋白抑制剂）对ERBT和咪达唑仑（一种非p糖蛋白底物）CYP3A介导代谢的影响。在8名健康受试者中进行了一项随机、双盲、双向交叉试验，其中包括在2个研究天内静脉给药安慰剂或tariquar （150 mg / 30分钟），间隔2周。在这两天，进行了1小时的ERBT，随后测定了咪达唑仑在1 mg后的全身清除率；静脉dose.Results。Tariquidar增加了ER。所有受试者的BT 1小时值(中位数，2.1%[四分位数间距（IQR）， 1.9%至3.3%]，安慰剂组和塔奎达组分别为5.4%[四分位数间距，3.7%至7.8%]；P = 0.012)，中位数增加2.3倍（IQR, 1.9- 3.0倍）。相比之下，咪达唑仑在他魁地尔后的全身清除率没有变化（中位变化，-4.6% [IQR, -10.2%至10.7%];P = 0.78）。肝p -糖蛋白是ERBT的重要决定因素，也是解释性状测量意义的潜在混淆因素。此外，研究结果还证实了肝脏药物代谢与双CYP3A/ p糖蛋白底物转运之间的动态相互作用。
Background. The erythromycin breath test (ERBT) has been widely used as a phenotypic measure of cytochrome P450 (CYP) 3A activity in individuals, as well as its modulation by inhibitors or inducers. However, it is not entirely dear what this measure actually reflects because, in addition to CYP3A, animal studies suggest that P-glycoprotein is also involved in erythromycin's hepatic disposition. Thus studies were undertaken to determine the effect of tariquidar, a potent P-glycoprotein inhibitor that does not affect CYP3A activity, on the ERBT and on the CYP3A-mediated metabolism of midazolam, a non-P-glycoprotein substrate.Methods. A randomized, double-blind, 2-way crossover trial was performed in 8 healthy subjects involving the intravenous administration of either placebo or tariquidar (150 mg over a period of 30 minutes) on 2 study days 2 weeks apart. On both days, a 1-hour ERBT was performed, followed by determination of midazolam's systemic clearance after a 1-mg; intravenous dose.Results. Tariquidar increased the ER.BT 1-hour value in all subjects (median, 2.1% [interquartile range (IQR), 1.9% to 3.3%] versus 5.4% [IQF, 3.7% to 7.8%] for placebo and tariquidar, respectively; P = .012), representing a median 2.3-fold (IQR, 1.9- to 3.0-fold) increase. By contrast, midazolam's systemic clearance after tariquidar was unchanged (median change, -4.6% [IQR, -10.2% to 10.7%]; P = .78).Conclusions. Hepatic P-glycoprotein is an important determinant of the ERBT and a potentially confounding factor in interpreting the meaning of the trait measure. In addition, the results demonstrate the dynamic interplay between hepatic drug metabolism and transport of dual CYP3A/P-glycoprotein substrates.