Niro Ryan, Byers James P, Fournier Ronald L, Bachmann Kenneth
Department of Bioengineering, The University of Toledo, Toledo, Ohio, USA.
Curr Drug Metab. 2003 Oct;4(5):357-69. doi: 10.2174/1389200033489334.
Growing interest in the prediction of in vivo pharmacokinetic data from purely in vitro data has grown into a process known as the in vitro-in vivo correlation (IVIC). IVIC can be used to determine the viability of new chemical entities in the early drug development phases, leading to a reduction of resource spending by many large pharmaceutical companies. Here, a convective-dispersion model was developed to predict the total hepatic clearance of six drugs using pharmacokinetic data obtained from in vitro metabolism studies in which the drug disappearance from suspensions of human cryopreserved hepatocytes was measured. Predicted in vivo hepatic clearances estimated by the convective-dispersion model were ultimately compared to the actual clearance values and to in vivo hepatic clearances that were scaled based on the well-stirred model. Finally, sensitivity studies were performed to determine the dependence of hepatic clearance on a number of physiological model parameters. Results reaffirmed that low clearance drugs exhibit rate-limited metabolism, and their hepatic clearances are thus independent of blood flow characteristics, whereas drugs with relatively higher clearance values show a more pronounced dependence on the flood flow properties of dispersion and convection. Absent a priori knowledge about the flow-dependent properties of a drug's clearance, the convective dispersion model applied to disappearance data acquired from cryopreserved human hepatocytes is likely to provide satisfactory estimates of hepatic drug clearance.
从纯体外数据预测体内药代动力学数据的兴趣日益浓厚，已发展成为一个被称为体外-体内相关性（IVIC）的过程。IVIC可用于在药物研发早期阶段确定新化学实体的可行性，从而使许多大型制药公司减少资源投入。在此，开发了一种对流-弥散模型，利用从体外代谢研究中获得的药代动力学数据预测六种药物的肝脏总清除率，在该研究中测量了药物从人冷冻保存肝细胞悬液中的消失情况。最终将对流-弥散模型估计的预测体内肝脏清除率与实际清除率值以及基于充分搅拌模型缩放的体内肝脏清除率进行比较。最后，进行敏感性研究以确定肝脏清除率对一些生理模型参数的依赖性。结果再次证实，低清除率药物表现出速率限制代谢，因此其肝脏清除率与血流特征无关，而清除率值相对较高的药物对弥散和对流的血流特性表现出更明显的依赖性。在缺乏关于药物清除率的流量依赖性特性的先验知识的情况下，应用于从冷冻保存的人肝细胞获得的消失数据的对流弥散模型可能会提供令人满意的肝脏药物清除率估计值。
