Liposome Electrokinetic Chromatography Method For Quantitative Retention Activity Off

A facile method for evaluating acidic drug-biomembrane interaction was established by liposome electrokinetic chromatography(LEKC). LEKC is a capillary electrophoresis technique where liposome is incorporated into a buffer solution and act as a pseudo-stationary phase using the structure similarity of liposome and biomembrane. Liposome-water partition coefficient(K_1w)of ferulic acid was determined in several minutes.The effect of cholesterol content,buffer pH and buffer composition on K_1wwas investigated respectively.An increase in cholesterol content(0%～30%)and pH values(4.00～12.00)resulted in a lower K_1w.In different buffer systems,the greater ionic strength was, the larger K_1wwas.The difference in K_1wrevealed ferulic acid-biomembrane interaction.LEKC is a good model evaluating the interaction of drug and biomembrane.Partition coefficients of neutral aromatic solutes in LEKC between 288 K～323 K were measured.A series of thermodynamic parameters were obtained by third-order polynomial fitting Van't Hoff plots.The thermodynamic partitioning behavior for those solutes was investigated.The results showed that the partition coefficient became greater with the increasing of temperature and the number of CH₂ functional group in benzene.During the whole experiment temperature(288 K～323 K),△H and T△S were positive while△G was negative,which indicated that the LEKC^- system of solutes partitioning into liposome was entropy-driven.From 288 K to 298 K,△C_P was negative and the LEKC partitioning system exhibited typical hydrophobic effect.From 303 K to 323 K,△C_P was positive and the LEKC partitioning system betrayed typical hydrophobic effect.A linear relationship between△H and△S indicated the occurrence of enthalpy-entropy compensation in LEKC system.LEKC provides a simple and facile approach for drug membrane interactions using liposome as a pseudostationary phase.This study evaluated the potential of LEKC for high-throughput skin permeability profiling as an in vitro technique.Quantitative retention-activity relationship(QRAR)model for the estimation of skin permeability was proposed.For the 16 structurally diverse chemicals,log k correlated well with permeability values(r²=0.886).The predictive ability of the model was evaluated by cross-validation.The result was compared to traditional quantitative structure-activity relationship,QSAR,models using some molecular descriptors and physicochemical parameters.Interestingly,a single LEKC retention parameter was capable of describing the skin permeability,while three variables in QSAR were needed to achieve a similar correlation(r²=0.704).The QRAR models developed in this paper may be a useful method to screening new chemicals and in the early stage of development and selection of chemicals.An investigation of the use of the retention in LEKC as an in vitro approach to predict the ecotoxicity is proposed.The ecotoxicity parameters(LC₅₀in fish,daphnia and mysid shrimp,EC₅₀in green algae and daphnia,and values of chronic ecotoxicity in fish and green algae)for 15 aromatic compounds were extracted from ECOTOX database from U.S.Environmental Protection Agency.QRAR models for the estimation of ecotoxicity were established.The r² of the fitted linear equations ranged from 0.80 to 0.87,which suggested good corralation between the retention in LEKC and the ecotoxicity parameters.The predictive ability of the models was evaluated by cross-validation.The results obtained indicated the usefulness of the LEKC systems investigated for the rapid ecotoxicity assessment of aromatic compounds.