کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2485350 | 1114352 | 2008 | 18 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Simulation Modelling of Human Intestinal Absorption using Caco-2 Permeability and Kinetic Solubility Data for Early Drug Discovery
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کلمات کلیدی
Solubility - انحلال پذیریIntestinal absorption - جذب رودهGastrointestinal transit - حمل و نقل معدهIn silico modeling - در مدل سازی سیلیکاCaco-2 cells - سلول های Caco-2Pharmacokinetics - فارماکوکینتیکnonlinear pharmacokinetics - فارماکوکینتیک غیرخطیMathematical model - مدل ریاضیPhysiological model - مدل فیزیولوژیکیin vitro/in vivo correlations (IVIVC) - همبستگی in vitro / in vivo (IVIVC)
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Measurement of permeation across a monolayer of the human adenocarcinoma cell line, Caco-2, is a popular surrogate for a compound's permeation across the human intestinal epithelium. Taken alone, however, Caco-2 permeability has certain limitations in the prediction of the extent of absorption of an orally-administered compound, because it does not take into account confounding factors such as solubility and dissolution in the gastrointestinal (GI) tract fluids. A simulation model is described that uses Caco-2 permeability measured in the apical to basolateral direction plus kinetic solubility in buffered solution (both measured at pH 7.4) to predict human intestinal absorption. The model features novel treatment of time-varying fluid volume in the GI tract, as a consequence of secretions into, and absorption of fluid from, the upper part of the GI tract. The model has been trained and cross-validated with data for 120 combinations of compound and dose. It has superior predictive power to recently published simulation and quantitative structure property relationship models, and is suitable for high-throughput screening during lead identification and lead optimisation in drug discovery.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 97, Issue 10, October 2008, Pages 4557-4574
Journal: Journal of Pharmaceutical Sciences - Volume 97, Issue 10, October 2008, Pages 4557-4574
نویسندگان
Simon Thomas, Frances Brightman, Helen Gill, Sally Lee, Boris Pufong,