Lennernäs Hans
Department of Pharmaceutics, Uppsala University, Sweden.
Eur J Pharm Sci. 2014 Jun 16;57:333-41. doi: 10.1016/j.ejps.2013.08.025. Epub 2013 Aug 27.
Over the last 25 years, profound changes have been seen in both the development and regulation of pharmaceutical dosage forms, due primarily to the extensive use of the biopharmaceutical classification system (BCS) in both academia and industry. The BCS and the FDA scale-up and post-approval change guidelines were both developed during the 1990s and both are currently widely used to claim biowaivers. The development of the BCS and its wide acceptance were important steps in pharmaceutical science that contributed to the more rational development of oral dosage forms. The effective permeation (Peff) of drugs through the intestine often depends on the combined outcomes of passive diffusion and multiple parallel transport processes. Site-specific jejunal Peff cannot reflect the permeability of the whole intestinal tract, since this varies along the length of the intestine, but is a useful approximation of the fraction of the oral dose that is absorbed. It appears that drugs with a jejunal Peff>1.5×10(-4)cm/s will be completely absorbed no matter which transport mechanisms are utilized. In this paper, historical clinical data originating from earlier open, single-pass perfusion studies have been used to calculate the Peff of different substances from sites in the jejunum and ileum. More exploratory in vivo studies are required in order to obtain reliable data on regional intestinal drug absorption. The development of experimental and theoretical methods of assessing drug absorption from both small intestine and various sites in the colon is encouraged. Some of the existing human in vivo data are discussed in relation to commonly used cell culture models. It is crucial to accurately determine the input parameters, such as the regional intestinal Peff, as these will form the basis for the expected increase in modeling and simulation of all the processes involved in GI drug absorption, thus facilitating successful pharmaceutical development in the future. It is suggested that it would be feasible to use open, single-pass perfusion studies for the in vivo estimation of regional intestinal Peff, but that care should be taken in the study design to optimize the absorption conditions.
在过去25年里，药物剂型的研发和监管都发生了深刻变化，这主要归因于生物药剂学分类系统（BCS）在学术界和工业界的广泛应用。BCS和美国食品药品监督管理局（FDA）的放大生产及批准后变更指南均在20世纪90年代制定，目前都被广泛用于申请生物豁免。BCS的发展及其广泛接受是药物科学中的重要步骤，有助于口服剂型的更合理开发。药物通过肠道的有效渗透率（Peff）通常取决于被动扩散和多个并行转运过程的综合结果。空肠特定部位的Peff不能反映整个肠道的通透性，因为其沿肠道长度会有所变化，但它是口服剂量吸收部分的有用近似值。似乎空肠Peff>1.5×10(-4)cm/s的药物无论采用何种转运机制都会被完全吸收。在本文中，源自早期开放、单通道灌注研究的历史临床数据已被用于计算空肠和回肠部位不同物质的Peff。为了获得关于肠道局部药物吸收的可靠数据，需要更多探索性的体内研究。鼓励开发评估小肠和结肠不同部位药物吸收的实验和理论方法。结合常用的细胞培养模型讨论了一些现有的人体体内数据。准确确定输入参数（如肠道局部Peff）至关重要，因为这些将构成胃肠道药物吸收所有相关过程建模和模拟预期增加的基础，从而促进未来成功的药物开发。建议使用开放、单通道灌注研究进行肠道局部Peff的体内估计是可行的，但在研究设计中应注意优化吸收条件。
