Alteration of the intravenous pharmacokinetics of a synthetic ozonide antimalarial in the presence of a modified cyclodextrin

✍ Scribed by Susan A. Charman; Christine S. Perry; Francis C.K. Chiu; Kylie A. McIntosh; Richard J. Prankerd; William N. Charman

• Publisher: John Wiley and Sons
• Year: 2006
• Tongue: English
• Weight: 184 KB
• Volume: 95
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.20534

✦ Synopsis

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 beta-cyclodextrin derivative (SBE(7)-beta-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.