Huh Yeamin, Smith David E, Feng Meihau Rose
Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan, USA.
Xenobiotica. 2011 Nov;41(11):972-87. doi: 10.3109/00498254.2011.598582. Epub 2011 Sep 5.
Human clearance prediction for small- and macro-molecule drugs was evaluated and compared using various scaling methods and statistical analysis. Human clearance is generally well predicted using single or multiple species simple allometry for macro- and small-molecule drugs excreted renally. The prediction error is higher for hepatically eliminated small-molecules using single or multiple species simple allometry scaling, and it appears that the prediction error is mainly associated with drugs with low hepatic extraction ratio (Eh). The error in human clearance prediction for hepatically eliminated small-molecules was reduced using scaling methods with a correction of maximum life span (MLP) or brain weight (BRW). Human clearance of both small- and macro-molecule drugs is well predicted using the monkey liver blood flow method. Predictions using liver blood flow from other species did not work as well, especially for the small-molecule drugs.
使用各种缩放方法和统计分析对小分子和大分子药物的人体清除率预测进行了评估和比较。对于经肾脏排泄的大分子和小分子药物，使用单物种或多物种简单异速生长法通常能很好地预测人体清除率。对于经肝脏消除的小分子药物，使用单物种或多物种简单异速生长缩放法时预测误差较高，并且似乎预测误差主要与肝脏提取率（Eh）低的药物有关。使用校正了最大寿命（MLP）或脑重量（BRW）的缩放方法可降低经肝脏消除的小分子药物人体清除率预测中的误差。使用猴肝血流量法能很好地预测小分子和大分子药物的人体清除率。使用其他物种的肝血流量进行的预测效果不佳，尤其是对于小分子药物。
