https://scholars.lib.ntu.edu.tw/handle/123456789/329552
標題: | Prediction and mechanistic interpretation of human oral drug absorption using MI-QSAR analysis | 作者: | Iyer, Manisha Senese, C. L. Liu, Jianzhong Hopfinger, A. J. YUFENG JANE TSENG |
關鍵字: | Membrane barrier transport; MI-QSAR analysis; Oral drug absorption | 公開日期: | 2007 | 卷: | 4 | 期: | 2 | 起(迄)頁: | 218-231 | 來源出版物: | Molecular Pharmaceutics | 摘要: | Membrane-interaction [MI]-QSAR analysis, which includes descriptors explicitly derived from simulations of solutes [drugs] interacting with phospholipid membrane models, was used to construct QSAR models for human oral intestinal drug absorption. A data set of 188 compounds, which are mainly drugs, was divided into a parent training set of 164 compounds and a test set of 24 compounds. Stable, but not highly fit [R2 = 0.68] MI-QSAR models could be built for all 188 compounds. However, the relatively large number [47] of drugs having 100% absorption, as well as all zwitterionic compounds [11], had to be eliminated from the training set in order to construct a linear five-term oral absorption diffusion model for 106 compounds which was both stable [R 2 = 0.82, Q2 = 0.79] and predictive given the test set compounds were predicted with nearly the same average accuracy as the compounds of the training set. Intermolecular membrane-solute descriptors are essential to building good oral absorption models, and these intermolecular descriptors are displaced in model optimizations and intramolecular solute descriptors found in published oral absorption QSAR models. A general form for all of the oral intestinal absorption MI-QSAR models has three classes of descriptors indicative of three thermodynamic processes: (1) solubility and partitioning, (2) membrane-solute interactions, and (3) flexibility of the solute and/or membrane. The intestinal oral absorption MI-QSAR models were compared to MI-QSAR models previously developed for Caco-2 cell permeation and for blood-brain barrier penetration. The MI-QSAR models for all three of these ADME endpoints share several common descriptors, and suggest a common mechanism of transport across all three barriers. A further analysis of these three types of MI-QSAR models has been done to identify descriptor-term differences across these three models, and the corresponding differences in thermodynamic transport behavior of the three barriers. © 2007 American Chemical Society. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-34247397960&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/329552 |
ISSN: | 15438384 | DOI: | 10.1021/mp0600900 | SDG/關鍵字: | adefovir; aminophenazone; amoxicillin; amphetamine; amrinone; atenolol; bornaprine; camazepam; captopril; cicaprost; cimetidine; codeine; corticosterone; diazepam; dihydrocodeine; disulfiram; ethambutol; famciclovir; famotidine; flecainide; lansoprazole; levodopa; methyldopa; naproxen; nisoldipine; nitrendipine; ouabain; oxprenolol; reproterol; unindexed drug; article; data analysis; drug absorption; drug diffusion; drug mechanism; drug research; drug solubility; drug structure; intestine absorption; molecular interaction; molecular weight; phospholipid membrane; priority journal; quantitative structure activity relation; Administration, Oral; Cell Membrane Permeability; Forecasting; Humans; Intestinal Absorption; Membranes, Artificial; Models, Molecular; Molecular Structure; Pharmaceutical Solutions; Phospholipids; Quantitative Structure-Activity Relationship |
顯示於: | 生醫電子與資訊學研究所 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。