Rapid induction of P-glycoprotein expression by high permeability compounds in colonic cells in vitro: a possible source of transporter mediated drug interactions?
Rapid induction of P-glycoprotein expression by high permeability compounds in colonic cells in vitro: a possible source of transporter mediated drug interactions?
复制标题
DOI：
10.1016/j.bcp.2004.05.006
复制
发表时间：
2004-08-15
影响因子：
5.8
通讯作者：
Warhurst, G
中科院分区：
文献类型：
--
作者：
Collett, A;Tanianis-Hughes, J;Warhurst, G
具有高膜渗透性的P-糖蛋白（PGP）底物，如普萘洛尔和维拉帕米，被认为对PGP基本上是"透明的"，因为转运蛋白不会显著限制它们的吸收或消除。然而，这类化合物是否可以调节PGP表达上皮细胞短期暴露后，与药物相互作用的潜在后果的问题，还没有得到解决。LS 180结肠上皮细胞暴露于普萘洛尔或维拉帕米的浓度（50 - 300 M）一致的那些可能存在于肠腔中口服给药。这两种化合物刺激MDR1 mRNA和PGP蛋白表达增加四到六倍，分别通过定量实时PCR和免疫印迹法测量。这些变化伴随着诱导的转运活性测定罗丹明123流出。与此相反，美托洛尔，一种具有相似渗透性但对PGP没有亲和力的化合物，对PGP表达没有影响。普萘洛尔和维拉帕米对PGP的诱导作用迅速，3 h内显著增加，6 h后刺激最大。利福平，通过PXR介导的PGP表达的增加，导致临床药物相互作用，表现出非常相似的时间过程和程度induction.In结论，维拉帕米和普萘洛尔，其跨上皮渗透性不受PGP的影响，似乎是有效的诱导剂PGP在体外肠上皮细胞的表达。虽然这些观察结果在体内的意义是未知的，这是否高渗透性的问题，“PGP透明”的化合物，目前在药物选择策略中的青睐，应评估其潜在的转运介导的药物相互作用。(C)2004年爱思唯尔公司All rights reserved.
P-glycoprotein (PGP) substrates with high membrane permeability, such as propranolol and verapamil, are considered to be essentially "transparent" to PGP since the transporter does not significantly limit their absorption or elimination. However, the question of whether such compounds can modulate PGP expression in epithelial cells following short-term exposure, with potential consequences for drug interactions, has not been addressed.LS180 colonic epithelial cells were exposed to propranolol or verapamil at concentrations (50-300 M) consistent with those likely to be present in the gut lumen during oral dosing. Both compounds stimulated four to six-fold increases in MDR1 mRNA and PGP protein expression measured by quantitative real-time PCR and immunoblotting, respectively. These changes were accompanied by an induction in transporter activity measured by rhodamine 123 efflux. In contrast, metoprolol, a compound with similar permeability but no affinity for PGP had no effect on PGP expression. The induction of PGP by propranolol and verapamil was rapid with significant increases occurring within 3 h with maximal stimulation after 6 h exposure. Rifampicin, shown to cause clinical drug interactions via a PXR-mediated increase in PGP expression, exhibited a very similar time-course and extent of induction.In conclusion, verapamil and propranolol, whose trans-epithelial permeability are unaffected by PGP, appear to be effective inducers of PGP expression in gut epithelial cells in vitro. While the in vivo significance of these observations is unknown, this questions whether high permeability, "PGP-transparent" compounds, currently favoured in drug selection strategies, should be evaluated in terms of their potential for transporter-mediated drug interactions. (C) 2004 Elsevier Inc. All rights reserved.