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首页> 外文期刊>Journal of pharmaceutical sciences. >Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage.
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Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage.

机译：建立体外P-糖蛋白抑制试验及其排除标准，以评估在药物发现阶段药物与药物相互作用的风险。

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The decision tree to determine whether the P-glycoprotein (P-gp)/multidrug resistance protein 1 (MDR1)-mediated drug-drug interaction (DDI) study is recommended has been proposed by the International Transporter Consortium. We, therefore, designed an in vitro P-gp inhibition assay and determined the appropriate risk criteria for P-gp-mediated DDI at the drug discovery stage. Effects of P-gp inhibitors on digoxin transport across a monolayer of MDR1-expressing cells were examined. The IC(50) (half-maximal inhibitory concentration) values generated from the efflux ratio (ER) were smaller than those generated from basolateral-to-apical directional apparent permeability. The difference in IC(50) values was kinetically described in a compartment model analysis. This analysis indicated that ER is a highly sensitive parameter that can be used for the degree of P-gp inhibition. Considering IC(50) values and the increase in digoxin exposure in clinical DDI studies, the risk criteria of [I(2)]/IC(50) = 30 ([I(2)], theoretically maximal gastrointestinal concentration) was the optimal cutoff value to predict a clinically relevant DDI. We also investigated whether the IC(50) value itself is applicable to assess the DDI risk. In conclusion, compounds with IC(50) values less than 2 muM exhibit high risk for P-gp-mediated DDIs. However, compounds with IC(50) values greater than or equal to 2 muM are inconclusive because clinical doses should be considered for the precise DDI risk assessment.
机译：国际运输者协会已经提出了确定是否推荐使用P-糖蛋白（P-gp）/多药耐药蛋白1（MDR1）介导的药物-药物相互作用（DDI）研究的决策树。因此，我们设计了体外P-gp抑制试验，并在药物发现阶段确定了P-gp介导的DDI的适当风险标准。检查了P-gp抑制剂对地高辛跨表达MDR1的单层细胞转运地高辛的影响。由流出比（ER）产生的IC（50）（半数最大抑制浓度）值小于由基底外侧至顶端的表观渗透率产生的值。在隔室模型分析中动力学描述了IC（50）值的差异。该分析表明ER是可用于P-gp抑制程度的高度敏感的参数。考虑到IC（50）值和临床DDI研究中地高辛暴露的增加，[I（2）] / IC（50）= 30（[I（2）]，理论上最大胃肠道浓度）的风险标准为最佳预测临床相关DDI的临界值。我们还调查了IC（50）值本身是否适用于评估DDI风险。总之，IC（50）值小于2μM的化合物显示P-gp介导的DDI的高风险。但是，IC（50）值大于或等于2μM的化合物尚无定论，因为对于精确的DDI风险评估应考虑临床剂量。

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