Interactions of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen with P-glycoprotein and CYP3A
Interactions of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen with P-glycoprotein and CYP3A
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DOI：
10.1002/bdd.411
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发表时间：
2004-10-01
影响因子：
2.1
通讯作者：
von Moltke, LL
中科院分区：
文献类型：
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作者：
Bekaii-Saab, TS;Perloff, MD;von Moltke, LL
在transwell系统中使用Caco-2细胞单层研究了他莫昔芬、N-去甲基他莫昔芬和4-羟基他莫昔芬对P-糖蛋白转运的影响，并以罗丹明-123作为抑制研究的指示底物。这三种化合物在Caco-2单层中未表现出基底-顶端和顶端-基底方向之间的差异通量。抑制罗丹明-123转运的平均IC 50值为：他莫昔芬为29 mum; N-去甲基他莫昔芬为26 mum; 4-羟基他莫昔芬为7.4 mum。基于使用人肝微粒体的三唑仑羟基化作为指示反应的体外模型，还评价了这三种化合物作为人CYP 3A的潜在抑制剂。人肝微粒体中α-羟基-三唑仑和4-羟基-三唑仑形成的平均（+/-SE）IC 50值分别为：23.5（+/-3.9）和18.4（+/-5.3）μ m; N-去甲基他莫昔芬为10.2（+/-1.7）和9.2（+/-1.5）μ m; 4-羟基他莫昔芬为2.6（+/-0.5）和2.7（+/-0.3）μ m。因此，他莫昔芬、N-去甲基他莫昔芬和4-羟基他莫昔芬似乎不是P-糖蛋白转运的底物。然而，他莫昔芬有可能抑制P-糖蛋白介导的转运以及CYP 3A介导的代谢。主要代谢产物N-去甲基他莫昔芬和4-羟基他莫昔芬的抑制作用可能超过母体药物。他莫昔芬及其可能的代谢产物可能通过抑制药物转运和代谢而引起药物相互作用。这种可能性需要在临床研究中进一步评估。版权所有（C）2004约翰威利父子有限公司。
The effects of tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen on transport attributable to P-glycoprotein were studied using Caco-2 cell monolayers in a transwell system, with rhodamine-123 as an index substrate for inhibition studies. The three compounds did not demonstrate differential flux between basal-apical and apical-basal directions in Caco-2 monolayers. The mean IC50 values for inhibition of rhodamine-123 transport were: 29mum for tamoxifen; 26 mum for N-desmethyltamoxifen; and 7.4 mum for 4-hydroxytamoxifen. The three compounds were also evaluated as potential inhibitors of human CYP3A based on an in vitro model using triazolam hydroxylation by human liver microsomes as an index reaction. Mean (+/-SE) IC50 values versus formation of alpha-hydroxy-triazolam and 4-hydroxy-triazolam in human liver microsomes were, respectively: 23.5 (+/-3.9) and 18.4 (+/-5.3) mum for tamoxifen; 10.2 (+/-1.7) and 9.2 (+/-1.5) mum for N-desmethyltamoxifen; and 2.6 (+/-0.5) and 2.7 (+/-0.3) mum for 4-hydroxytamoxifen. Thus, tamoxifen, N-desmethyltamoxifen and 4-hydroxytamoxifen, do not appear to be substrates for transport by P-glycoprotein. However, tamoxifen has the potential to inhibit transport mediated by P-glycoprotein as well as CYP3A-mediated metabolism. Inhibitory effects of the principal metabolites, N-desmethyltamoxifen and 4-hydroxytamoxifen, may exceed those of the parent drug. Tamoxifen, and possibly its metabolites, may have the potential to cause drug interactions by inhibiting both drug transport and metabolism. This possibility requires further evaluation in clinical studies. Copyright (C) 2004 John Wiley Sons, Ltd.