Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2487152 | Journal of Pharmaceutical Sciences | 2006 | 12 Pages |
Abstract
The pharmacokinetic profile and renal clearance of a novel synthetic ozonide antimalarial (1) was found to be significantly altered when intravenously administered to rats as a cyclodextrin-based formulation (0.1 M Captisol®, a sulfobutylether β-cyclodextrin derivative (SBE7-β-CD)) compared to a cyclodextrin-free isotonic buffered glucose formulation. There was an 8.5-fold decrease in the steady-state blood volume of distribution, a 6.6-fold decrease in the mean residence time and a greater than 200-fold increase in renal clearance of 1 when administered in the cyclodextrin formulation. Analysis of the whole blood and plasma concentration profiles revealed an essentially constant blood to plasma ratio when 1 was administered in the cyclodextrin-free formulation, whereas this ratio changed as a function of time when administered in the presence of the cyclodextrin derivative. It is postulated that the observed differences were due to a very strong complexation interaction between 1 and the cyclodextrin, resulting in a slow dissociation of the complex in vivo, and altered distribution and excretion profiles. Preliminary studies using isothermal titration calorimetry (ITC) indicated that the association constant for the 1/Captisol® complex was approximately two orders of magnitude higher than reported for typical drug/cyclodextrin complexes. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association
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Authors
Susan A. Charman, Christine S. Perry, Francis C.K. Chiu, Kylie A. McIntosh, Richard J. Prankerd, William N. Charman,