Disposition mechanisms of raloxifene in the human intestinal Caco-2 model
Disposition mechanisms of raloxifene in the human intestinal Caco-2 model
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DOI：
10.1124/jpet.103.063925
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发表时间：
2004-07-01
影响因子：
3.5
通讯作者：
Hu, M
中科院分区：
文献类型：
--
作者：
Jeong, EJ;Lin, HM;Hu, M
本研究的目的是确定雷洛昔芬及其亲水性缀合物的转运机制。采用人肠道Caco-2细胞培养模型和Caco-2细胞裂解液进行研究。结果表明，雷洛昔芬的吸收通透性（P-AB）低于分泌通透性（P-BA）。随着浓度的增加，P-BA/P-AB的外排比降低，P-AB升高。两种p糖蛋白抑制剂维拉帕米和环孢素A存在时P-AB也增加。雷洛昔芬被广泛代谢成硫酸和葡萄糖醛酸缀合物。代谢或清除率随浓度从3.4（96%）增加到30（22%）而降低。多药耐药相关蛋白抑制剂MK-571 （C26H26ClN2O3S2）和白三烯C-4显著降低了这两种偶联物的顶端外排（最大达80%）。它们也显著减少（最大85%）葡萄糖醛酸盐的基底外侧外排，但硫酸盐没有。另一方面，有机阴离子转运体（OAT）抑制剂雌酮硫酸酯和雌酮葡萄糖醛酸盐显著降低（最大50%）两侧的硫酸盐外排，但对葡萄糖醛酸盐外排的影响不同。OAT抑制剂硫酸雌酮对共轭外排的抑制是浓度依赖性的，这导致完整雷洛昔芬的运输增加（最大90%）。在另一种OAT抑制剂雌酮葡萄糖醛酸盐存在时，也观察到雷洛昔芬转运增加（70%）。总之，这是首次报道抑制负责代谢物运输的外排转运蛋白可导致完整化合物运输增加。这也解释了为什么雷洛昔芬的生物利用度低，但半衰期长。
The purpose of this study was to determine the mechanisms responsible for transport of raloxifene and its hydrophilic conjugates. Human intestinal Caco-2 cell culture model and Caco-2 cell lysate were used for the studies. The results indicated that absorptive permeability (P-AB) of raloxifene was lower than its secretory permeability (P-BA). As the concentration increased, the efflux ratio (P-BA/P-AB) decreased, but P-AB increased. P-AB was also increased in the presence of verapamil and cyclosporine A, two P-glycoprotein inhibitors. Raloxifene was extensively metabolized into sulfated and glucuronidated conjugates. The extent of metabolism or clearance was decreased as the concentration increased from 3.4 (96%) to 30 (22%) muM. Multidrug resistance-related protein inhibitors MK-571 (C26H26ClN2O3S2) and leukotriene C-4 significantly decreased (maximal 80%) apical efflux of both conjugates. They also significantly decreased ( maximal 85%) basolateral efflux of glucuronides but not sulfates. On the other hand, organic anion transporter (OAT) inhibitor estrone sulfate and estrone glucuronide significantly decreased (maximal 50%) the efflux of sulfate from both sides but had variable effects on glucuronide efflux. Inhibition of conjugate efflux with the OAT inhibitor estrone sulfate was concentration dependent, which resulted in increased transport of intact raloxifene (maximal 90%). This increase in raloxifene transport was also observed in the presence of another OAT inhibitor estrone glucuronide (70%). In conclusion, this is the first report that inhibition of an efflux transporter responsible for the transport of metabolites can result in increase in the transport of the intact compound. It also provides additional explanation why raloxifene has low bioavailability but a long half-life.