Alteration of the intravenous pharmacokinetics of a synthetic
ozonide antimalarial in the presence of a modified cyclodextrin.
Centre for Drug Candidate Optimisation, Victorian
College of Pharmacy, Monash University (Parkville Campus), Parkville,
Victoria, Australia. email@example.com
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.
Copright 2005 Wiley-Liss, Inc.
PMID: 16374851 [PubMed - indexed for MEDLINE]