Quantitative retention-activity relationship models of angiotensin converting enzyme inhibitors using biopartitioning micellar chromatography.

Biopartitioning micellar chromatography (BMC) is a mode of micellar liquid chromatography that uses micellar mobile phases of Brij35 under adequate experimental conditions and can simulate biopartioning process of many kinds of drugs and describe their biological behavior. The capability of BMC to describe and estimate pharmacokinetic and pharmacodynamic parameters of angiotensin-converting enzyme inhibitors (ACEIs) had been studied in this paper. The correlation between retention factors of ACEIs obtained using BMC and bioactivity parameters (half-life, volume of distribution, clearance, and IC(50)) was investigated utilizing a second-order polynomial model. The P-values obtained for half-life, volume of distribution, clearance, and IC(50) models were less than 0.05, and the r(2) of those four models were 0.89, 0.98, 0.94, and 0.97, with r(2)(adj) (adjusted for freedom degrees) being 0.85, 0.98, 0.91, and 0.95, respectively. The predictive and interpretative ability of the chromatographic models was evaluated in terms of cross-validated data [root mean squared error of calibration (RMSEC), root mean squared error of cross-validation (leave-one-out) (RMSECV), and root mean squared error of cross-validation (leave-one-out) for interpolated data (RMSECVi)]. The quantitative retention-activity relationship (QRAR) models of ACEIs developed in this paper may be a useful approach to screening new chemicals in the early stage of development.

Mixed micellar liquid chromatography methods: modelling quantitative retention-activity relationships of angiotensin converting enzyme inhibitors.

The capability of biopartitioning micellar chromatography (BMC), using pure Brij35 solution and mixed micellar system of Brij35-SDS (85:15) as mobile phase, to describe and estimate bioactivities of angiotensin converting enzyme inhibitors at different pH has been studied. Quantitative retention-activity relationships (QRAR) in BMC were investigated for these compounds. The obtained BMC(Brij35-SDS)-QRAR models were compared with the traditional BMC(Brij35)-QRAR, and better statistically models were obtained using Brij35-SDS retention data. The superiority of BMC(Brij35-SDS)-QRAR is due to the fact that the mixed micellar mobile phase can simulate the resting membrane potential and the conformation of the long hydrophilic polyoxyethylene chains remains unchanged.

Development of predictive quantitative retention-activity relationship models of HMG-CoA reductase inhibitors by biopartitioning micellar chromatography.

Biological fluid cell membranes are barriers for the uptake of many kinds of drugs and their metabolites, along with passive transport across membranes and bioaccumulation. Biopartitioning micellar chromatography (BMC) is a mode of micellar liquid chromatography that uses micellar mobile phases of Brij35 under adequate experimental conditions and can be useful to simulate the drug's passive absorption and the transport in biological systems. The use of micellar aqueous solutions of Brij35 as mobile phases in reversed-phase liquid chromatography has proven to be valid to predict the biological activities of barbiturates, benzodiazepines, catecholamines, local anesthetics, non-steriodal anti-inflammatory drugs and tricyclic antidepressants. In this study, the relationships between the capacity factor in BMC and some pharmacokinetic and pharmacodynamic parameters of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are studied. Predictive quantitative retention-activity relationship (QRAR) models describing some of the biological activities and pharmacokinetic properties of HMG-CoA reductase inhibitors are obtained. The results indicate that QRAR model may be a useful tool during the drug discovery process.