SDS-Based Biomembrane Mimetic Chromatography for Prediction of Human Drug Transport as an in Vitro Technique

The main oral drug absorption barriers are fluid cell membranes, and generally drugs are absorbed by a passive diffusion mechanism. On the other hand, the blood–brain barrier (BBB) is considered to be the main barrier to drug transport into the central nervous system (CNS). The BBB restricts the passive diffusion of many drugs from blood to brain. Biopartitioning micellar chromatography (BMC), a mode of micellar liquid chromatography that uses micellar mobile phases in adequate experimental conditions, can be useful as an in vitro system in mimicking the drug partitioning process into biological systems. In this study, relationships between the BMC retention data of a heterogeneous set of 12 drugs and their pharmacokinetics parameters (human oral drug absorption and BBB penetration ability) are studied and the predictive ability of the models is evaluated. Modeling of log k _BMC of these compounds was established by multiple linear regression in two different concentrations (0.07 and 0.09 M) of sodium dodecyl sulfate (SDS). The results showed a fair correlation between human oral drug absorption and BMC retention data in 0.09 M SDS (R ² = 0.864) and a good correlation between the blood–brain distribution coefficient and BMC retention data in 0.07 M of SDS (R ² = 0.887). Application of the developed models to a prediction set demonstrated that the model is also reliable with good predictive accuracy. The external and internal validation results showed that the predicted values are in good agreement with the experimental value.     

SDS-Based Biomembrane Mimetic Chromatography for Prediction of Human Drug Transport as an in Vitro Technique

The main oral drug absorption barriers are fluid cell membranes, and generally drugs are absorbed by a passive diffusion mechanism. On the other hand, the blood–brain barrier (BBB) is considered to be the main barrier to drug transport into the central nervous system (CNS). The BBB restricts the passive diffusion of many drugs from blood to brain. Biopartitioning micellar chromatography (BMC), a mode of micellar liquid chromatography that uses micellar mobile phases in adequate experimental conditions, can be useful as an in vitro system in mimicking the drug partitioning process into biological systems. In this study, relationships between the BMC retention data of a heterogeneous set of 12 drugs and their pharmacokinetics parameters (human oral drug absorption and BBB penetration ability) are studied and the predictive ability of the models is evaluated. Modeling of log k _BMC of these compounds was established by multiple linear regression in two different concentrations (0.07 and 0.09 M) of sodium dodecyl sulfate (SDS). The results showed a fair correlation between human oral drug absorption and BMC retention data in 0.09 M SDS (R ² = 0.864) and a good correlation between the blood–brain distribution coefficient and BMC retention data in 0.07 M of SDS (R ² = 0.887). Application of the developed models to a prediction set demonstrated that the model is also reliable with good predictive accuracy. The external and internal validation results showed that the predicted values are in good agreement with the experimental value.

     

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.     

Quantitative structure-retention relationships for ionic and non-ionic compounds in biopartitioning micellar chromatography

Quantitative structure-retention relationships, QSRRs, represent a powerful tool in chromatography. The objectives of QSRR studies are to predict the chromatographic retention behaviour of solutes based on their structural properties, to elucidate retention mechanisms, to optimize the separation of complex mixtures or to prepare experimental designs. In this paper, using the retention factors of 151 structurally unrelated solutes that cover a wide range of hydrophobicity, molecular size, hydrogen bonding properties and ionization degrees obtained in biopartitioning micellar chromatography (BMC) at different Brij35 micellar concentrations, several multivariate QSRR models are tested. It is demonstrated that the chromatographic retention of any molecule in BMC, independently of its family, can be adequately described by its hydrophobicity (expressed as log P) and its anionic and cationic total molar charge (expressed as alpha(A) and alpha(B)).     

应用BMC理论方法预测选择性钙通道阻断剂药理学参数

The usefulness of biopartitioning micellar chromatography （BMC） for predicting oral drug acute toxicity and apparent bioavailability was demonstrated. A logarithmic model （an LD50 model） and the second order polynomial models （apparent bioavailability model） have been obtained using the retention data of the selective calcium channel blockers to predict pharmacological properties of compounds. The use of BMC is simple, reproducible and can provide key information about the acute toxicity and transport properties of new compounds during the drug discovery process.     

Profiling of Permeable Compounds in Ligusticum chuanxiong by Biopartitioning Micellar Chromatography

The potential of biopartitioning micellar chromatography (BMC) for screening and analysis of traditional Chinese medicines (TCM) for permeable compounds has been investigated by chromatography of methanolic extracts of Ligusticum chuanxiong, as example. Six other ordinary TCM were also studied. Results showed that more than ten components of Ligusticum chuanxiong extract are significantly retained in BMC. According to relationships between retention in BMC and oral drug absorption, cell-membrane permeability, and blood–brain barrier permeability, the cell-membrane permeability and absorption properties of the permeable components of Ligusticum chuanxiong extract could be predicted from their retention in BMC. Effects on the chromatography of components of Ligusticum chuanxiong methanolic extracts of column temperature, mobile phase pH, and concentration of Brij 35 in the mobile phase are also discussed.     

Development of predictive retention-activity models of butyrophenones by biopartitioning micellar chromatography

The predictive and interpretative capability of quantitative chromatographic retention-biological activity models is supported by the fact that in adequate experimental conditions the solute partitioning into the chromatographic system can emulate the solute partitioning into lipid bilayers of biological membranes, which is the basis of drug and metabolite uptake, passive transport across membranes and bioaccumulation. The use of retention data obtained in biopartitioning micellar chromatography (BMC) has been demonstrated to be helpful in describing the biological behaviour of different kinds of drugs. In this chromatographic system, polioxyethylene 23 lauryl ether Brij35 micellar mobile phases and C(18) reversed stationary phase in adequate experimental conditions are used. The RP-HPLC capacity factors of butyrophenones were determined using different Brij35 concentrations as micellar mobile phases. Relationships between seven biological activities of butyrophenones reported in bibliography and retention data were established and their predictive and interpretative ability evaluated. These relationships were significant between preclinical pharmacology and therapeutic efficacy parameters and the retention factors of butyrophenones (0.89 < R(2) < 0.98). The results indicate that the retention of compounds in BMC is capable of describing and predicting in vitro the biological activities of butyrophenones. This approach can be very useful in the development of new neuroleptic drugs, avoiding the use of experimental animals.     

Characterization of biopartitioning micellar chromatography system using monolithic column by linear solvation energy relationship and application to predict blood–brain barrier penetration

The linear solvation energy relationship (LSER) was applied to characterize biopartitioning micellar chromatography (BMC) system using monolithic column, and was utilized to compare the above system with other physicochemical and biological processes in this study. The solute volume and HB basicity had the maximum influence on the retention of the solutes, and an increase in the dipolarity/polarizability, HB basicity, HB acidity or excess molar refraction of the solutes decreased the retention. Principal component analysis of LSER coefficients showed that the system had certain similarity to drug biomembrane transport processes, such as blood–brain barrier penetration, transdermal and oral absorption. The quantitative retention–activity relationship (QRAR) of drug penetration across blood–brain barrier was established and its predictive capability for this biological process was evaluated. With the aid of the high flow rate, the monolithic column significantly facilitated the high-throughput analysis of large compounds’ bank without changing the mechanism of the retention in BMC and without impairing good predictive capability of the biological processes. Accordingly, the BMC system, together with monolithic column, allows for high-throughput profiling the biological processes, such as blood–brain barrier penetration.     

An LD50 model for predicting psychotropic drug toxicity using biopartitioning micellar chromatography

The LD50 determination is the main way to measure the acute toxicity of all types of substances. At the present time, however, there is increasing opposition to the use of living animals in research and testing activities from animal rights groups as well as some scientists. Nevertheless, the need to have a tool for estimating the potential toxicity of new compounds for human consumption has encouraged the development of alternative methods. Under adequate conditions, the partitioning in micellar liquid chromatography can describe the drug biopartitioning. We have named this chromatographic system biopartitioning micellar chromatography (BMC). In this paper, an LD50 QRAR model developed for psychotropic drugs from their retention data in BMC, is described. The model's ability to predict new psychotropic drug toxicity is statistically proved.     

Recent methodological and instrumental development in MEKC

The review gives an update about the methodological and instrumental developments in micellar electrokinetic capillary chromatography as a type of CE analytical technique. Here, the last two years development of the technique are particularly presented. Recent approaches to improve sensitivity are discussed. Newly introduced concentration techniques and experimental methods for verification of the different mechanisms and processes of micellar electrokinetic chromatography analysis are highlighted. A theoretical model to explain changes in separation and electrophoretic mobility order of fully charged analytes are demonstrated. Modern approaches for improving compatibility of micellar electrokinetic capillary chromatography to mass spectrometry are also reported.     

Fast profiling ecotoxicity and skin permeability of benzophenone ultraviolet filters using biopartitioning micellar chromatography based on penetrable silica spheres

Penetrable silica possesses hierarchical pores, mesopores and penetrable macropores, offering fast mass transfer, satisfactory mechanical strength as well as low column pressure. In the present study, penetrable octadecyl-bonded silica (ODS) was for the first time used as biopartitioning micellar chromatography (BMC) stationary phase to profile ecotoxicity and skin permeability of benzophenone UV-filters. Mobile phase (MP) pH and concentration of polyoxyethylene(23)lauryl ether in the MP were systematically studied. Quantitative retention–activity relationships (QRARs) model was established to correlate retention factors (k) on BMC with bioconcentration factor (BCF) and transdermal rate (TR) of UV-filters. Coefficient of determination (r²) of the QRARs model between log BCF and log k were 0.9398–0.9753, while r² between TR and log k were 0.7569–0.8434, which demonstrated satisfactory predictive ability of the methodology. It was a powerful tool for fast screening by combining penetrable ODS with BMC, and avoiding column blockage often occurring in BMC.     

Efficiency of antidepressant drugs as monoamine reuptake inhibitors: analysis of the hydrophobicity influence using biopartitioning micellar chromatographic data

The reuptake blockade of biogenic amines by antidepressants is related not only to their therapeutics effects, but also to their side effects and potential drug-drug interactions. As an alternative to classical quantitative structure-activity relationships studies, in this work we propose different quantitative retention-activity relationships (QRAR) models that are able to describe the monoamine reuptake inhibition by antidepressants. The retention of compounds is measured using a biopartitioning micellar chromatography (BMC) system that can simulate the same hydrophobic, electronic and steric molecular interactions as those that condition drug activity. Since all the compounds considered in this work are structurally related because all of them share the same molecular features as the corresponding basic pharmacophore, the results obtained show that there is a retention range in which antidepressants present the highest monoamine reuptake inhibitor potency.     

Quantitative Structure-Retention Relationship Studies with Biopartitioning Micellar Chromatography Systems by Amended Linear Solvation Energy Relationships in Consideration of Electronic Factor

Linear solvation energy relationship (LSER) amended by the introduction of a molecular electronic factor was employed to establish quantitative structure-retention relationship of biopartitioning micellar chromatography (BMC) system. The chromatographic indices, log k, were determined by LC on a C18 column for sixty-five structurally diverse compounds, including neutral (32), acidic (19) and basic (14) compounds. Two micellar mobile phases composed of 0.04 mol L^?1 polyoxyethylene (23) lauryl ether (Brij35) were adjusted by phosphate buffer to pH 7.4 and pH 6.5, respectively. When the mean net charge per molecule (δ) was introduced into LSER as the sixth variable, the LSER regression coefficients and predictive capability were significantly improved. However, the δ coefficients of the amended LSER were quite different for acidic and basic compounds, indicating that the molecular electronic factor had a markedly different impact on the retention of acidic and basic compounds in the studied BMC system. This may attribute to the extra interaction for ionized compounds with the free silanol groups in the stationary phase. The comparison of calculated and experimental retention indices suggested that the amended LSER could reproduce adequately the retention of the structurally diverse solutes investigated in BMC.     

Permeability and toxicological profile estimation of organochlorine compounds by biopartitioning micellar chromatography

This paper points out the usefulness of biopartitioning micellar chromatography (BMC) as a high-throughput primary screening tool providing key information about the oral absorption, skin permeability (K(p)), brain-blood distribution coefficient (BB) and ecotoxicological parameters such as median lethal concentration (LC(50)) and bioconcentration factors of 15 organochloride compounds. The retention data of compounds in BMC conditions were interpolated in previously developed quantitative-retention activity relationships by our research group. Results show that the compounds studied readily cross the intestinal barrier (oral absorption > 90%) and the blood-brain barrier (log BB > 0.4). In addition, the organochlorines DDE, chlorobenzene, 1,3-dichlorobenzene and 1,2-dichlorobenzene are the compounds which can more quickly cross the skin barrier (log K(p ) > -0.74 cm/h). From a ecotoxicological point of view, it can be concluded that the most retained compounds, DDE, DDD, hexachlorobenzene and dicofol, are the most toxic and bioacumulative.     

Retention modeling in micellar liquid chromatography

The aim of this review is to present the most relevant work on retention modeling in micellar liquid chromatography. First, physico-chemical models explaining the variation of capacity factors with one or more experimental variables (such as micellar concentration, organic modifier concentration, and pH) will be shown. Secondly, studies carried out to model the solute retention in micellar liquid chromatography by means of empirical equations will be presented, and finally new trends in this area will be introduced.     

Mobile phase versus stationary phase approaches to the direct injection of biological fluids in liquid chromatography

The liquid chromatographic analysis of drugs in urine through direct injection without any sample pretreatment was extended to micellar chromatography with nonionic surfactants, the Pinkerton ISRP column and the shielded hydrophobic phase (Hisep) column. The feasibility of using each was demonstrated through the determination of the diuretic, hydrochlorothiazide, in urine. Good separation, recovery, precision and linearity, and adequate limits of detection were obtained for this analysis with all three techniques. The advantages and limitations of the mobile phase approach of micellar chromatography and the two stationary phase approaches are discussed for the direct injection of urine as well as other biological fluids.     

Recent and future trends in blood group typing

Blood group typing is the process of testing red blood cells to determine which antigens are present and which are absent. It is standard practice to test for A, B, and D (Rh) antigens and to perform tests for other antigens in selected cases. ABO blood group typing is confirmed by reverse grouping that detects expected isoagglutinins. Unexpected antibodies can be demonstrated by antibody screening tests. For transfusion, donor units compatible with the patient are selected. Prior to transfusion, a crossmatch is performed as a final check for incompatibility. This article describes the recent and future methods of blood group typing and testing of serological compatibility. In addition, methods for blood bank automation are presented.