Stoner Chad L, Cleton Adriaan, Johnson Kjell, Oh Doo-Man, Hallak Hussein, Brodfuehrer Joanne, Surendran Narayanan, Han Hyo-Kyung
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105, USA.
Int J Pharm. 2004 Jan 9;269(1):241-9. doi: 10.1016/j.ijpharm.2003.09.006.
The objective of the analysis described herein is to examine the in vitro/in vivo relationship of estimated bioavailability values and also the applicability of the estimated in vitro bioavailability to lead candidate selection in drug discovery. To this end, in vitro ADME data from screening assays as well as in vivo rat pharmacokinetic (PK) data were compiled for 140 compounds across therapeutic areas from the Pfizer library in Ann Arbor. The compounds span a broad range of structural types, including neutral, basic, and acidic compounds. Solubility and Caco-2 permeability data from in vitro ADME screening were used to calculate the fraction dose absorbed (FDp) using the physiologically based IDEA model. In vitro metabolic stability (t(1/2)) from human and rat liver microsomal incubations was converted to an in vitro intrinsic clearance value (CL(int)'), which was then scaled up to reflect in vivo clearance (CL) and hepatic extraction as described by Obach et al. [J. Pharmcol. Exp. Ther. 283 (1997) 46]. Subsequently, the in vitro/in vivo relationship between the measured bioavailability (F(obs)) in rats and the estimated bioavailability (F(est)) from FDp and predicted CL values was examined. The observed data suggest that compounds with low estimated in vitro bioavailability (F(est)<15%) are more likely to have low in vivo bioavailability (F(obs)<30%). Therefore, the present study indicates that in vitro estimation of bioavailability is an efficient tool to eliminate compounds having low bioavailability prior to in vivo characterization and therefore can be used to reduce attrition due to poor ADME properties in drug development.
本文所述分析的目的是研究估计的生物利用度值的体外/体内关系，以及估计的体外生物利用度在药物发现中用于指导候选药物选择的适用性。为此，收集了来自安阿伯市辉瑞文库中140种跨治疗领域化合物的体外ADME筛选数据以及大鼠体内药代动力学（PK）数据。这些化合物涵盖了广泛的结构类型，包括中性、碱性和酸性化合物。利用体外ADME筛选得到的溶解度和Caco-2通透性数据，采用基于生理学的IDEA模型计算吸收剂量分数（FDp）。将人和大鼠肝微粒体孵育的体外代谢稳定性（t(1/2)）转换为体外固有清除率值（CL(int)'），然后按照Obach等人[《药理学与实验治疗学杂志》283 (1997) 46]所述进行放大，以反映体内清除率（CL）和肝脏提取率。随后，研究了大鼠体内实测生物利用度（F(obs)）与根据FDp和预测CL值估计的生物利用度（F(est)）之间的体外/体内关系。观察到的数据表明，估计的体外生物利用度较低（F(est)<15%）的化合物更有可能具有较低的体内生物利用度（F(obs)<30%）。因此，本研究表明，生物利用度的体外估计是一种有效的工具，可在体内表征之前排除生物利用度低的化合物，从而可用于减少药物开发中因ADME性质差导致的损耗。
