کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2486308 1114380 2006 13 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
The binding interaction of synthetic ozonide antimalarials with natural and modified β-cyclodextrins
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
The binding interaction of synthetic ozonide antimalarials with natural and modified β-cyclodextrins
چکیده انگلیسی
The current studies were undertaken to explore the potential basis for a significant difference in the pharmacokinetic parameters after intravenous administration of a synthetic ozonide (OZ) antimalarial drug candidate (1) to rats when formulated in either Captisol® (a sulfobutylether substituted β-cyclodextrin derivative ((SBE)7-β-CD)) or a buffered aqueous vehicle. It was suspected that the differences may have been due to failure of 1 to rapidly dissociate from the cyclodextrin complex in vivo, perhaps due to an unusually tight binding within the cyclodextrin cavity. To address this hypothesis, the binding of representative synthetic OZ antimalarial drug candidates (including 1) with β-cyclodextrin and (SBE)7-β-CD was investigated by isothermal titration calorimetry and phase solubility analysis. It was found that each of the OZ compounds exhibited an exceptionally high binding constant (∼106/M) with both Cyclodextrins (CD). The nature of the complexation was investigated by molecular dynamics simulations and NMR to explore the mechanisms, which generated such high binding constants. The data suggested that the most probable cause of the unusually high binding constants was a very close fit within the cyclodextrin cavity that resulted in more favourable changes in both the enthalpy and entropy of the binding interaction, compared to published data for other drugs. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 95, Issue 1, January 2006, Pages 146-158
نویسندگان
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