Jung Seo Jeong, Choi Sun Ok, Um So Young, Kim Joo Il, Choo Hae Young Park, Choi Su Young, Chung Soo Youn
Division of Biopharmaceutics, Department of Pharmacology, National Institute of Toxicological Research, Korea Food and Drug Administration, #231 Jinheungno, Eunpyung-Gu, Seoul, Republic of Korea.
J Pharm Biomed Anal. 2006 May 3;41(2):469-75. doi: 10.1016/j.jpba.2005.12.020. Epub 2006 Feb 3.
This study is to research the quantitative structure-permeability relationship of 20 drugs having similar structure. Permeability was determined by using the Caco-2 cell in vitro model. The apparent permeability coefficient (Papp) of each drug both of apical to basolateral side and basolateral to apical side was measured at the concentration corresponding to 0.1 times the highest dose strength of 250 mL dissolved buffer. In order to test the permeability system suitability, we measured the Papp of 19 model drugs out of 20 which presented in 'Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms based on the Biopharmaceutics Classification System' of FDA guidance. Also, we demonstrated the functional expression of efflux systems (e.g., p-gp) by bi-directional transport studies with rhodamine 123. Also, as a result of the study on quantitative structure-permeability relationship by using the partial least square method, it was possible to predict the permeability of drugs from their 3D structure. The quantitative structure-permeability relationship provided a cross-validated q2=0.789, a normal r2=0.998. Considering all of above results, analysis on this quantitative structure-permeability relationship appears to be a very useful tool to predict the permeability.
本研究旨在探讨20种结构相似药物的定量构效关系。采用Caco-2细胞体外模型测定通透性。在对应于250 mL溶解缓冲液中最高剂量强度0.1倍的浓度下，测量每种药物从顶侧向基底侧以及从基底侧向顶侧的表观渗透系数（Papp）。为了测试渗透系统的适用性，我们测量了FDA指南中“基于生物药剂学分类系统的速释固体口服制剂体内生物利用度和生物等效性研究的豁免”中列出的20种模型药物中的19种的Papp。此外，我们通过用罗丹明123进行双向转运研究，证明了外排系统（如p-gp）的功能表达。而且，作为使用偏最小二乘法进行定量构效关系研究的结果，可以从药物的三维结构预测其通透性。定量构效关系提供了交叉验证的q2 = 0.789，常规r2 = 0.998。考虑到上述所有结果，对这种定量构效关系的分析似乎是预测通透性的非常有用的工具。
