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首页> 美国卫生研究院文献>Drug Metabolism and Disposition >Use of Mechanistic Modeling to Assess Interindividual Variability and Interspecies Differences in Active Uptake in Human and Rat Hepatocytes
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Use of Mechanistic Modeling to Assess Interindividual Variability and Interspecies Differences in Active Uptake in Human and Rat Hepatocytes

机译：使用机制模型评估人和大鼠肝细胞主动摄取的个体差异和种间差异

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摘要

Interindividual variability in activity of uptake transporters is evident in vivo, yet limited data exist in vitro, confounding in vitro-in vivo extrapolation. The uptake kinetics of seven organic anion-transporting polypeptide substrates was investigated over a concentration range in plated cryopreserved human hepatocytes. Active uptake clearance (CLactive, u), bidirectional passive diffusion (Pdiff), intracellular binding, and metabolism were estimated for bosentan, pitavastatin, pravastatin, repaglinide, rosuvastatin, telmisartan, and valsartan in HU4122 donor using a mechanistic two-compartment model in Matlab. Full uptake kinetics of rosuvastatin and repaglinide were also characterized in two additional donors, whereas for the remaining drugs CLactive, u was estimated at a single concentration. The unbound affinity constant (Km, u) and Pdiff values were consistent across donors, whereas Vmax was on average up to 2.8-fold greater in donor HU4122. Consistency in Km, u values allowed extrapolation of single concentration uptake activity data and assessment of interindividual variability in CLactive across donors. The maximal contribution of active transport to total uptake differed among donors, for example, 85 to 96% and 68 to 87% for rosuvastatin and repaglinide, respectively; however, in all cases the active process was the major contributor. In vitro-in vivo extrapolation indicated a general underprediction of hepatic intrinsic clearance, an average empirical scaling factor of 17.1 was estimated on the basis of seven drugs investigated in three hepatocyte donors, and donor-specific differences in empirical factors are discussed. Uptake Km, u and CLactive, u were on average 4.3- and 7.1-fold lower in human hepatocytes compared with our previously published rat data. A strategy for the use of rat uptake data to facilitate the experimental design in human hepatocytes is discussed.
机译：体内摄取转运蛋白活性的个体差异是很明显的，但是体外数据有限，混淆了体外-体内外推法。研究了七种有机阴离子转运多肽底物在平板冷冻保存的人类肝细胞中的浓度范围内的吸收动力学。使用Matlab的机械两室模型，评估了HU4122供体中的波生坦，匹伐他汀，普伐他汀，瑞格列奈，瑞舒伐他汀，替米沙坦和缬沙坦的主动摄取清除率（CLactive，u），双向被动扩散（Pdiff），细胞内结合和代谢。瑞舒伐他汀和瑞格列奈的完全吸收动力学在另外两个供体中也得到了表征，而对于其余的CLactive药物，u估计为单一浓度。供体的未结合亲和力常数（Km，u）和Pdiff值一致，而供体HU4122中的Vmax平均高出2.8倍。 Km，u值的一致性允许外推单个浓度摄取活动数据并评估供体之间CLactive的个体间变异性。主动转运对总摄取的最大贡献在供体之间有所不同，例如瑞舒伐他汀和瑞格列奈分别为85％至96％和68％至87％；但是，在所有情况下，积极的过程都是主要的贡献者。体外-体内推断表明一般会低估肝脏的内在清除率，在三位肝细胞供体中研究的七种药物的基础上，平均经验比例因子估计为17.1，并讨论了经验因子的供体特异性差异。与我们先前发表的大鼠数据相比，人肝细胞中的Km，u和CLactive摄取u平均分别低4.3和7.1倍。讨论了使用大鼠摄取数据促进人类肝细胞实验设计的策略。

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