Wils P, Warnery A, Phung-Ba V, Scherman D
UMR 133 CNRS/RPR, Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Cell Biol Toxicol. 1994 Dec;10(5-6):393-7. doi: 10.1007/BF00755788.
The oral absorption of a compound is a critical factor for the future of the compound as a drug. This absorption is mainly controlled by the passage across the intestinal epithelium. Thus, the prediction of the intestinal absorption by means of an in vitro model may represent a powerful tool for the early selection of molecules during the process of drug development. In the present study, the differentiated human intestinal epithelial cell line HT29-18-C1, was grown on permeable filters in dual chambers. These cells formed tight monolayers that were used to measure in vitro the transepithelial permeability coefficient (Pc) of various molecules. The results were compared with in vivo data of oral absorption. A threshold value of in vitro permeability of 2 x 10(-6) cm/s was found. Molecules having a permeability coefficient higher than this value were absorbed orally more than 80%, while drugs with Pc values lower than 2 x 10(-6) cm/s were poorly absorbed. By mathematical simulation, it was found that this Pc value, when extrapolated to the surface area and volume of the small intestine, corresponds to an absorption of 80% for a compound with a transit time through the small intestine of 5 h. This demonstrates the predictive utility of the threshold value of the permeability coefficient derived from the in vitro model of intestinal epithelium.
化合物的口服吸收是其作为药物未来发展的关键因素。这种吸收主要受跨肠上皮细胞的转运控制。因此，借助体外模型预测肠道吸收可能是药物开发过程中早期筛选分子的有力工具。在本研究中，分化的人肠上皮细胞系HT29-18-C1在双室的可渗透滤膜上生长。这些细胞形成紧密单层，用于体外测量各种分子的跨上皮渗透系数（Pc）。将结果与口服吸收的体内数据进行比较。发现体外渗透率的阈值为2×10^(-6) cm/s。渗透系数高于该值的分子口服吸收率超过80%，而Pc值低于2×10^(-6) cm/s的药物吸收较差。通过数学模拟发现，当将该Pc值外推至小肠的表面积和体积时，对于在小肠中转运时间为5小时的化合物，其吸收率为80%。这证明了从肠上皮体外模型得出的渗透系数阈值的预测效用。
