Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2486308 | Journal of Pharmaceutical Sciences | 2006 | 13 Pages |
Abstract
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 (â¼106/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
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Authors
Christine S. Perry, Susan A. Charman, Richard J. Prankerd, Francis C.K. Chiu, Martin J. Scanlon, David Chalmers, William N. Charman,