在Vitro-In Transporter-based体内外推(IVIVE)

文摘
使用体外数据来预测药物的药代动力学(PK)由转运蛋白是谁的性格是复杂由于未知的转运蛋白表达水平在个人组织体内以及各种体外细胞培养系统。被动扩散的贡献之间的药物传输个人组织细胞外和细胞内空间是另一个需要考虑的重要方面较低的药物通过细胞膜渗透性和缓慢的扩散。permeability-surface区域产品(PStc)通常用于描述通过膜被动扩散的速度。估计PStc值不同的组织纳入PBPK模型不完善由于未知的个人组织的生理方面,例如,细胞表面区域。我们提出一个新的方法来描述不同组织的被动扩散通过扩展PStc值组织细胞卷。进一步扩展该方法估计的贡献被动和carrier-mediated运输体内体外测量。缬沙坦作为模型化合物分布和间隙依赖运输活动。GastroPlusTM7.0与其PBPK PlusTM模块(模拟+,Inc .,兰开斯特,CA)是用来模拟等离子体浓度时间(Cp-time)档案利用基于生理药代动力学(PBPK)模型对动物和人类的生理机能。药物分区到细胞外空间被一个extracellular-water:等离子体分配系数,考虑结合药物血浆和细胞外组织蛋白质。Carrier-mediated交通动力学在肝脏估计之前报道体外培养肝细胞的参数测量。 Passive diffusion between the extracellular and intracellular spaces in liver was described by PStc, which was also estimated from previously reported values measured in vitro. Passive diffusion in other tissues was described by PStc values scaled from the liver PStc according to individual tissue volumes. Simulations using a combination of kinetic parameters from the relevant in vitro system (cultured hepatocytes) with physiologically based scaling of the passive diffusion rate across all tissues resulted in very good prediction of total valsartan exposure and provided the correct shape of the predicted Cp-time profile in rat and human based on in silico and in vitro parameters. This method is a promising tool for prediction of the pharmacokinetics of drugs whose disposition cannot be described by well-stirred tissue models, and it expands the predictive capabilities of PBPK modelling approaches for prediction of pharmacokinetics based on in vitro data to a wider range of compounds.