Soars Matthew G, Grime Ken, Sproston Joanne L, Webborn Peter J H, Riley Robert J
Department of Physical and Metabolic Science, AstraZeneca Charnwood, Bakewell Road, Loughborough, Leics, LE11 5RH, England.
Drug Metab Dispos. 2007 Jun;35(6):859-65. doi: 10.1124/dmd.106.014464. Epub 2007 Mar 7.
The wealth of information that has emerged in recent years detailing the substrate specificity of hepatic transporters necessitates an investigation into their potential role in drug elimination. Therefore, an assay in which the loss of parent compound from the incubation medium into hepatocytes ("media loss" assay) was developed to assess the impact of hepatic uptake on unbound drug intrinsic clearance in vivo (CL(int ub in vivo)). Studies using conventional hepatocyte incubations for a subset of 36 AstraZeneca new chemical entities (NCEs) resulted in a poor projection of CL(int ub in vivo) (r2 = 0.25, p = 0.002, average fold error = 57). This significant underestimation of CL(int ub in vivo) suggested that metabolism was not the dominant clearance mechanism for the majority of compounds examined. However, CL(int ub in vivo) was described well for this dataset using an initial compound "disappearance" CL(int) obtained from media loss assays (r2 = 0.72, p = 6.3 x 10(-11), average fold error = 3). Subsequent studies, using this method for the same 36 NCEs, suggested that the active uptake into human hepatocytes was generally slower (3-fold on average) than that observed with rat hepatocytes. The accurate prediction of human CL(int ub in vivo) (within 4-fold) for the marketed drug transporter substrates montelukast, bosentan, atorvastatin, and pravastatin confirmed further the utility of this assay. This work has described a simple method, amenable for use within a drug discovery setting, for predicting the in vivo clearance of drugs with significant hepatic uptake.
近年来涌现出的大量信息详细说明了肝脏转运体的底物特异性，因此有必要对它们在药物消除中的潜在作用进行研究。为此，开发了一种检测方法，即检测孵育介质中母体化合物进入肝细胞的损失情况（“介质损失”检测法），以评估肝脏摄取对体内未结合药物内在清除率（CL(int ub in vivo)）的影响。对阿斯利康36种新化学实体（NCE）中的一部分进行的传统肝细胞孵育研究，对CL(int ub in vivo)的预测效果不佳（r2 = 0.25，p = 0.002，平均倍数误差 = 57）。对CL(int ub in vivo)的这种显著低估表明，代谢并非大多数所检测化合物的主要清除机制。然而，使用从介质损失检测中获得的初始化合物“消失”CL(int)，该数据集的CL(int ub in vivo)得到了很好的描述（r2 = 0.72，p = 6.3 x 10(-11)，平均倍数误差 = 3）。随后使用相同方法对这36种NCE进行的研究表明，人类肝细胞的主动摄取通常比大鼠肝细胞慢（平均3倍）。对市售药物转运体底物孟鲁司特、波生坦阿托伐他汀和普伐他汀的人体CL(int ub in vivo)（误差在4倍以内）的准确预测，进一步证实了该检测方法的实用性。这项工作描述了一种简单的方法，适用于药物发现环境，用于预测具有显著肝脏摄取的药物的体内清除率。
