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

• Published in: Journal of pharmaceutical sciences Vol. 95; no. 2; pp. 256 - 267
• Main Authors: Charman, Susan A., Perry, Christine S., Chiu, Francis C.K., McIntosh, Kylie A., Prankerd, Richard J., Charman, William N.
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.02.2006; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Animals; Antimalarials - chemical synthesis; Antimalarials - pharmacokinetics; Antimalarials - urine; Biological and medical sciences; Calorimetry; complexation; cyclodextrins; Cyclodextrins - chemistry; Cyclodextrins - metabolism; distribution; General pharmacology; Injections, Intravenous; Male; Medical sciences; Molecular Conformation; Ozone - chemistry; Pharmaceutical Preparations; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; renal clearance; Reproducibility of Results; Time Factors; pharmacokinetics; renal clearance; distribution; complexation; cyclodextrins; Antimalarial; Complexation; Pharmaceutical technology; Intravenous administration; Clearance; Kidney; Cyclodextrin; Distribution; Parasiticide; Inclusion compound; Pharmacokinetics
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20534

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 (0.1M 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