Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin
Interactions of human P-glycoprotein with simvastatin, simvastatin acid, and atorvastatin
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DOI：
10.1023/b:pham.0000041466.84653.8c
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发表时间：
2004-09-01
影响因子：
3.7
通讯作者：
Prueksaritanont, T
中科院分区：
文献类型：
--
作者：
Hochman, JH;Pudvah, N;Prueksaritanont, T
目的.本研究通过观察P-糖蛋白（P-gp）介导的辛伐他汀（SV）、辛伐他汀酸（SVA）和阿托伐他汀（AVA）的外排以及SV、SVA和AVA对P-gp的抑制作用，探讨P-gp在药物相互作用中的作用。通过跨LLC-PK 1细胞和转染人MDR 1的LLC-PK 1细胞单层的定向转运来确定P-gp介导的SV、SVA和AVA的外排。通过研究SV、SVA和AVA浓度高达50 μ M时Caco-2细胞和P-gp过表达KBV 1细胞中长春碱外排来评价P-gp的抑制作用。定向转运研究显示，对于SVA和AVA，P-gp介导的SV外排不显著，P-gp转运中度[基底外侧（B）至顶端（A）转运比A至B转运高2.4-3.8和3.0-6.4]。SV和AVA对P-gp的抑制作用（IC_（50）与25 -50 μ M相似），而SVA对P-gp无抑制作用。与全身药物水平相比，中等水平的P-gp介导转运和SV、SVA和AVA对P-gp抑制的低亲和力表明，由于竞争P-gp转运而引起的药物相互作用不太可能是药物不良相互作用的重要因素。此外，SV、SVA和AVA的P-gp抑制研究与P-gp转运之间的不一致性表明，抑制研究不是鉴别他汀类药物为Pgp底物的有效方法。
Purpose. In this study, P-glycoprotein (P-gp) mediated efflux of simvastatin (SV), simvastatin acid (SVA), and atorvastatin (AVA) and inhibition of P-gp by SV, SVA, and AVA were evaluated to assess the role of P-gp in drug interactions.Methods. P-gp mediated efflux of SV, SVA, and AVA was determined by directional transport across monolayers of LLC-PK1 cells and LLC-PK1 cells transfected with human MDR1. Inhibition of P-gp was evaluated by studying the vinblastine efflux in Caco-2 cells and in P-gp overexpressing KBV1 cells at concentrations of SV, SVA, and AVA up to 50 muM.Results. Directional transport studies showed insignificant P-gp mediated efflux of SV, and moderate P-gp transport [2.4-3.8 and 3.0-6.4 higher Basolateral (B) to Apical (A) than A to B transport] for SVA and AVA, respectively. Inhibition studies did not show the same trend as the transport studies with SV and AVA inhibiting P-gp (IC50 similar to25-50 muM) but SVA not showing any inhibition of P-gp.Conclusions. The moderate level of P-gp mediated transport and low affinity of SV, SVA, and AVA for P-gp inhibition compared to systemic drug levels suggest that drug interactions due to competition for P-gp transport is unlikely to be a significant factor in adverse drug interactions. Moreover, the inconsistencies between P-gp inhibition studies and P-gp transport of SV, SVA, and AVA indicate that the inhibition studies are not a valid means to identify statins as Pgp substrates.