کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2486175 1114377 2011 10 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Effect of gastric pH on the pharmacokinetics of a bcs class II compound in dogs: Utilization of an artificial stomach and duodenum dissolution model and gastroplus,™ simulations to predict absorption
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
Effect of gastric pH on the pharmacokinetics of a bcs class II compound in dogs: Utilization of an artificial stomach and duodenum dissolution model and gastroplus,™ simulations to predict absorption
چکیده انگلیسی
Dogs are one of the most commonly used non‐rodent species in toxicology studies and are known to have basal stomach pH ranging from 2 to 7 in the fasted state. Thus absorption and resulting plasma exposure of weakly basic compounds administered as crystalline suspensions to dogs are often variable. LY2157299 is a potent and selective transforming growth factor (TGF)‐beta receptor type 1 kinase (TGF‐βRI) inhibitor that displayed variable absorption in early dog studies. This molecule is a weakly basic Biopharmaceutics Classification System (BCS)Class II compound, and depends on the rate and extent of dissolution to drive oral absorption. An artificial stomach and duodenum (ASD) dissolution model was utilized to evaluate potential effect of gastric pH on the absorption of suspension and buffered solution formulations. GastroPlus™ was also employed to predict the magnitude of gastric pH changes on LY2157299 absorption. The ASD experiments demonstrated that administration of a buffered acidic solution could improve the potential for absorption by normalizing gastric pH and enabling supersaturation in the duodenum. GastroPlus™ modeling suggested that direct modulation of gastric pH could lead to marked changes in bioavailability. Pharmacokinetic experiments were conducted in dogs to evaluate the effect of gastric pH modification on plasma exposure. The data were qualitatively consistent with the predictions. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4756-4765, 2011
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 100, Issue 11, November 2011, Pages 4756-4765
نویسندگان
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