Validation of a total IC50 method which enables in vitro assessment of transporter inhibition under semi-physiological conditions
Validation of a total IC50 method which enables in vitro assessment of transporter inhibition under semi-physiological conditions
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DOI：
10.1080/00498254.2016.1233372
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发表时间：
2017-01-01
期刊：
影响因子：
1.8
通讯作者：
Bow, Daniel A. J.
中科院分区：
文献类型：
--
作者：
Kikuchi, Ryota;Peterkin, Vincent C.;Bow, Daniel A. J.
1.当化合物溶解性差和/或非特异性结合高时，从体外数据准确预测临床转运蛋白介导的药物-药物相互作用（DDI）可能具有挑战性。此外，如果实验值小于0.01或无法确定，则目前对血浆蛋白结合率高的化合物的DDI预测假定血浆中的未结合分数为0.01。这种方法可能会导致DDI风险的高估。为了克服这些挑战，在生理学相关条件下进行抑制研究可能是有益的。在此，在接近人血浆白蛋白浓度的4%牛血清白蛋白存在下测定的IC 50值成功用于预测摄取转运蛋白OATP 1B 1/1B 3、OCT 1/2、OAT 1/3和MATE 1/2K。含有4%牛血清白蛋白的参比抑制剂的IC 50值（视为总IC 50）与基于在无蛋白条件下测定的标称IC 50值和血浆中未结合分数的预测值相当。使用总血浆暴露量和总IC 50值计算R-总和C-max/IC 50，总值解释了这些抑制剂的临床DDI或不存在DDI。这些结果表明，在临床总暴露量的背景下，在存在4%白蛋白的情况下测定IC 50可用于预测涉及摄取转运蛋白的DDI。
1.Accurate predictions of clinical transporter-mediated drug-drug interactions (DDI) from in vitro data can be challenging when compounds have poor solubility and/or high nonspecific binding. Additionally, current DDI predictions for compounds with high plasma-protein binding assume that the unbound fraction in plasma is 0.01, if the experimental value is less than 0.01 or cannot be determined. This approach may result in an overestimation of DDI risk. To overcome these challenges, it may be beneficial to conduct inhibition studies under physiologically relevant conditions.Here, IC50 values, determined in the presence of 4% bovine serum albumin approximating human plasma albumin concentrations, were successfully used to predict DDI for uptake transporters, OATP1B1/1B3, OCT1/2, OAT1/3 and MATE1/2K.The IC50 values of reference inhibitors with 4% bovine serum albumin, considered total IC50, were comparable to the predicted values based on nominal IC50 values determined under protein-free conditions and unbound fraction in plasma. Calculation of R-total and C-max/IC50,total values using total plasma exposure and total IC50 values explained the clinical DDI or absence of it for these inhibitors.These results suggest that IC50 determinations in the presence of 4% albumin can be used, in the context of clinical total exposure, to predict DDI involving uptake transporters.