Alteration of the intravenous pharmacokinetics of a synthetic ozonide antimalarial in the presence of a modified cyclodextrin.
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.
Charman
Susan A
SA
Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria, Australia. susan.charman@vcp.monash.edu.au
Perry
Christine S
CS
Chiu
Francis C K
FC
McIntosh
Kylie A
KA
Prankerd
Richard J
RJ
Charman
William N
WN
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000652:urine; D002151:Calorimetry; D003505:Cyclodextrins / Q000737:chemistry* / Q000378:metabolism*; D007275:Injections, Intravenous; D008297:Male; D008968:Molecular Conformation; D010126:Ozone / Q000737:chemistry*; D004364:Pharmaceutical Preparations; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013997:Time Factors
D000962:Antimalarials; D003505:Cyclodextrins; D004364:Pharmaceutical Preparations; D010126:Ozone