Publications by authors named "Christine S Perry"

4 Publications

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Chemical kinetics and aqueous degradation pathways of a new class of synthetic ozonide antimalarials.

J Pharm Sci 2006 Apr;95(4):737-47

Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University, Parkville Campus, Victoria 3052, Australia.

Chemical stability of a new class of ozonide (1,2,4 trioxolanes) antimalarial compounds was investigated. The effects of pH, ionic strength, dielectric constant and cyclodextrin-complexation on the chemical stability and degradation product formation of selected compounds were examined. The mechanism of degradation in aqueous solution was probed using (18)O-labelled water and kinetic solvent isotope effect studies. The effect of stereochemistry was investigated using selected pairs of stereoisomers. The degradation of the ozonides in aqueous solution followed apparent first-order kinetics, with no effect of ionic strength and no indication of any direct involvement of water in the degradation mechanism. All major degradation products were identified and mass balance was confirmed. Stereochemistry had a significant effect on degradation rate; trans isomers degrading approximately four-fold faster than the corresponding cis isomers. The degradation rates were essentially independent of pH above pH 2; however, an additional specific acid catalysed pathway was dominant below pH 2. Solvent dielectric constant had a significant effect on the degradation rate. It is proposed that the degradation observed in aqueous solution occurred through a concerted heterolytic scission of the central ozonide ring, with chemical substituents on the cyclohexyl ring having only a minor influence on degradation rate.
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http://dx.doi.org/10.1002/jps.20568DOI Listing
April 2006

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

J Pharm Sci 2006 Feb;95(2):256-67

Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University (Parkville Campus), Parkville, Victoria, Australia.

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.
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http://dx.doi.org/10.1002/jps.20534DOI Listing
February 2006

The binding interaction of synthetic ozonide antimalarials with natural and modified beta-cyclodextrins.

J Pharm Sci 2006 Jan;95(1):146-58

Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University, Parkville Campus, 381 Royal Parade, Parkville, Victoria 3052, Australia.

The current studies were undertaken to explore the potential basis for a significant difference in the pharmacokinetic parameters after intravenous administration of a synthetic ozonide (OZ) antimalarial drug candidate (1) to rats when formulated in either Captisol (a sulfobutylether substituted beta-cyclodextrin derivative ((SBE)(7)-beta-CD)) or a buffered aqueous vehicle. It was suspected that the differences may have been due to failure of 1 to rapidly dissociate from the cyclodextrin complex in vivo, perhaps due to an unusually tight binding within the cyclodextrin cavity. To address this hypothesis, the binding of representative synthetic OZ antimalarial drug candidates (including 1) with beta-cyclodextrin and (SBE)(7)-beta-CD was investigated by isothermal titration calorimetry and phase solubility analysis. It was found that each of the OZ compounds exhibited an exceptionally high binding constant ( approximately 10(6)/M) with both Cyclodextrins (CD). The nature of the complexation was investigated by molecular dynamics simulations and NMR to explore the mechanisms, which generated such high binding constants. The data suggested that the most probable cause of the unusually high binding constants was a very close fit within the cyclodextrin cavity that resulted in more favourable changes in both the enthalpy and entropy of the binding interaction, compared to published data for other drugs.
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http://dx.doi.org/10.1002/jps.20525DOI Listing
January 2006

Partitioning of halofantrine hydrochloride between water, micellar solutions, and soybean oil: Effects on its apparent ionization constant.

J Pharm Sci 2003 Nov;92(11):2217-28

Centre for Drug Candidate Optimisation, Victorian College of Pharmacy, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia.

Recent studies in a conscious dog model demonstrated intestinal lymphatic transport to be a significant contributor to the bioavailability of the highly lipid-soluble free-base of halofantrine (Hf), and surprisingly, also the poorly lipid-soluble hydrochloride salt (Hf. HCl). Partial conversion of solubilized Hf. HCl to Hf base within the intestinal lumen prior to the lymphatic uptake seemed to be the most likely explanation for these results. This hypothesis was supported by studies exploring the partitioning behavior of Hf. HCl between soybean oil (SBO) and aqueous micellar solutions containing different ionic and nonionic surfactants. Mixed micelles prepared from sodium taurodeoxycholate (NaTC) and lecithin (PC) were chosen to represent fed-state intestinal fluids. The apparent ionization constants derived from the partitioning versus pH profiles showed marked shifts when compared with the likely aqueous pK(a) value. In the present paper, the apparent pK(a) values of Hf in aqueous micellar phases, without a coexisting oil phase, were investigated to further probe the mechanisms underlying the effect of micellar media on the apparent ionization equilibrium, and subsequently, on its partitioning behavior in the triphasic systems. Another aim of this study was to further evaluate the aqueous pK(a) value of Hf. The results indicate that the aqueous pK(a) of Hf is most probably in the range approximately 8-9, and that the ionization equilibrium is highly dependent on the solution environment. For example, marked pK(a) shifts of several units were observed for Hf in the presence of different micellar species and SBO. The apparent ionization equilibrium depends not only on interaction of Hf with the micelles, but also on its partitioning into the oil phase.
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http://dx.doi.org/10.1002/jps.10479DOI Listing
November 2003