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INTRODUCTION: Immobilized artificial membrane (IAM) chromatography is widely used in many aspects of drug discovery. It employs stationary phases, which contain phospholipids combining simulation of biological membranes with rapid measurements. AREAS COVERED: Advances in IAM stationary phases, chromatographic conditions and the underlying retention mechanism are discussed. The potential of IAM chromatography to model permeability and drug-membrane interactions as well as its use to estimate pharmacokinetic properties and toxicity endpoints including ecotoxicity, is outlined. Efforts to construct models for prediction IAM retention factors are presented. EXPERT OPINION: IAM chromatography, as a border case between partitioning and binding, has broadened its application from permeability studies to encompass processes involving tissue binding. Most IAM-based permeability models are hybrid models incorporating additional molecular descriptors, while for the estimation of pharmacokinetic properties and binding to off targets, IAM retention is combined with other biomimetic properties. However, for its integration into routine drug discovery protocols, reliable IAM prediction models implemented in relevant software should be developed, to enable its use in virtual screening and the design of new molecules. Conversely, preparation of new IAM columns with different phospholipids or mixed monomers offers enhanced flexibility and the potential to tailor the conditions according to the target property.
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An analytical approach has been developed to verify the authenticity of premium lentils originating from Eglouvi, Lefkada, Greece. The method relies on the digestion of samples followed by the analysis of their rare earth elements (REEs) content. Lentils originating from Eglouvi exhibit higher content in most REEs compared to lentils from other regions as well as distinct Sc/Y and Sc/Yb concentration ratios. Principal component analysis effectively segregates "Eglouvi" lentils into a distinct cluster. Soft Independent Modelling of Class Analogy (SIMCA) successfully models "Eglouvi" lentils. Significant enhancement in model specificity was achieved upon inclusion of Sc/Y and Sc/Yb concentration ratios as additional variables. The model is capable of detecting adulteration in blends of Eglouvi lentils, with a minimum rejection threshold of 4.6% w/w for Greek lentil adulterants and 6.0% w/w for imported lentil adulterants.
Subject(s)
Lens Plant , Greece , ChemometricsABSTRACT
The development of high-throughput approaches for the valid estimation of brain disposition is of great importance in the early drug screening of drug candidates. However, the complexity of brain tissue, which is protected by a unique vasculature formation called the blood−brain barrier (BBB), complicates the development of robust in silico models. In addition, most computational approaches focus only on brain permeability data without considering the crucial factors of plasma and tissue binding. In the present study, we combined experimental data obtained by HPLC using three biomimetic columns, i.e., immobilized artificial membranes, human serum albumin, and α1-acid glycoprotein, with molecular descriptors to model brain disposition of drugs. Kp,uu,brain, as the ratio between the unbound drug concentration in the brain interstitial fluid to the corresponding plasma concentration, brain permeability, the unbound fraction in the brain, and the brain unbound volume of distribution, was collected from literature. Given the complexity of the investigated biological processes, the extracted models displayed high statistical quality (R2 > 0.6), while in the case of the brain fraction unbound, the models showed excellent performance (R2 > 0.9). All models were thoroughly validated, and their applicability domain was estimated. Our approach highlighted the importance of phospholipid, as well as tissue and protein, binding in balance with BBB permeability in brain disposition and suggests biomimetic chromatography as a rapid and simple technique to construct models with experimental evidence for the early evaluation of CNS drug candidates.
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Biomimetics , Brain , Biological Transport , Blood-Brain Barrier/metabolism , Brain/metabolism , Chromatography , Humans , Models, BiologicalABSTRACT
Fraction Lipophicity Index (FLI) has been developed as a composite drug-like metric combining log P and log D in a weighted manner. In the present study, an extended data set confirmed the previously established drug-like FLI range 0-8 using two calculation systems for log P/log D assessment, the freeware MedChem Designer and ClogP. The dataset was split into two classes according to the percentage of fraction absorbed (%FA) - class 1 including drugs with high to medium absorption levels and class 2 including poorly absorbed drugs. The FLI and FLI-C (ClogP based FLI) drug-like range covers 92 % and 91 % of class 1 drugs, respectively. Using MlogP, a narrower drug-like FLI-M range 0-7 was established, covering 91 % of class 1 drugs. The dependence of the degree of ionization to intrinsic lipophilicity within the FLI (FLI-C, FLI-M) drug-like range as well as the inter-relation between the other Ro5 properties (Mw, HD, HA) was explored to define drug-like / non-drug-like combinations as a safer alternative to single properties for drug candidates' prioritization. In this sense, we propose a combined metric of Mw and the number of polar atoms (Mw/NO) to account for both size and polarity. Setting the value 50 as cutoff, a distinct differentiation between class 1 and class 2 drugs was obtained with Mw/NO>50 for more than 70 % of class 1 drugs, while the opposite was observed for class 2 drugs.
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Introduction: In multi-objective drug design, optimization gains importance, being upgraded to a discipline that attracts its own research. Current strategies are broadly classified into single - objective optimization (SOO) and multi-objective optimization (MOO).Areas covered: Starting with SOO and the ways used to incorporate multiple criteria into it, the present review focuses on MOO techniques, their comparison, advantages, and restrictions. Pareto analysis and the concept of dominance stand in the core of MOO. The Pareto front, Pareto ranking, and limitations of Pareto-based methods, due to high dimensions and data uncertainty, are outlined. Desirability functions and the weighted sum approaches are described as stand-alone techniques to transform the MOO problem to SOO or in combination with pareto analysis and evolutionary algorithms. Representative applications in different drug research areas are also discussed.Expert opinion: Despite their limitations, the use of combined MOO techniques, as well as being complementary to SOO or in conjunction with artificial intelligence, contributes dramatically to efficient drug design, assisting decisions and increasing success probabilities. For multi-target drug design, optimization is supported by network approaches, while applicability of MOO to other fields like drug technology or biological complexity opens new perspectives in the interrelated fields of medicinal chemistry and molecular biology.
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Algorithms , Artificial Intelligence , Drug Design , HumansABSTRACT
Therapeutic interventions with aldose reductase inhibitors appear to be a promising approach to major pathological conditions (i.e. neuropathy/angiopathy related to chronic hyperglycemia, chronic inflammation and cancer). Until now, the most potent aldose reductase inhibitors have been carboxylic acid derivatives, which poorly permeate biological membranes. In this work, continuing our previous works, we promote the bioisosteric replacement of the carboxylic acid moiety to make equally potent yet more druggable inhibitors.
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Aldehyde Reductase/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Indoles/chemistry , Phenols/chemistry , Sulfones/chemistry , Aldehyde Reductase/chemistry , Aldehyde Reductase/metabolism , Animals , Catalytic Domain , Drug Design , Enzyme Assays , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Indoles/chemical synthesis , Indoles/metabolism , Molecular Docking Simulation , Phenols/chemical synthesis , Phenols/metabolism , Protein Binding , Rats , Sulfones/chemical synthesis , Sulfones/metabolismABSTRACT
In the present study, 88 structurally- diverse drugs were investigated by biopartitioning micellar chromatography (BMC) using Brij-35 as surfactant under different chromatographic conditions. It was found that temperature and presence of NaCl have only a minor effect in BMC retention. Correlation of BMC retention factors with octanol-water partitioning required the inclusion of fractions of ionized species as additional parameters, showing that there is a weaker effect of ionization in BMC environment. Compared to Immobilized Artificial Membrane (IAM) Chromatography, BMC retention factors cover a relatively narrow span, two-fold smaller than retention factors on IAM stationary phases as a result of the presence of micelles facilitating elution of lipophilic compounds and the absence of secondary attractive electrostatic interactions in the BMC environment. Similarities/dissimilarities between BMC, octanol-water partitioning and IAM Chromatography were investigated by Linear Free Energy Relationships (LSER). BMC retention factors were used to construct relationships with cell permeability,% Human Oral Absorption (%HOA) and Plasma Protein Binding (%PPB). Linear BMC models were obtained with Caco-2 cell lines and Parallel Artificial Membrane Permeability Assay (PAMPA). For %HOA, a hyperbolic model was established upon incorporation of topological polar surface area (tPSA) as additional parameter. A sigmoidal model was constructed for %PPB and a linear one for the corresponding thermodynamic binding constant logK. In both cases inclusion of the fraction of anionic species with a positive sign was required reflecting the preference of human albumin for acidic drugs.
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Chromatography, Liquid , Models, Biological , Pharmaceutical Preparations/metabolism , Absorption, Physiological , Blood Proteins/metabolism , Caco-2 Cells , Cell Membrane Permeability , Humans , Linear Models , Membranes, Artificial , Micelles , Octanols/chemistry , Polyethylene Glycols/chemistry , Surface-Active Agents/chemistry , Thermodynamics , Water/chemistrySubject(s)
Chromatography/methods , Drug Development/methods , Membranes, Artificial , Animals , Drug Discovery/methods , HumansABSTRACT
Introduction: Fragment screening is a successful approach to accelerate drug discovery. Since it handles fragments with weak affinity, sensitive analytical tools are strongly demanded. Areas covered: After a short description of the available techniques employed in fragment screening, this review focuses on Weak Affinity Chromatography (WAC). Details include the origins of affinity chromatography and its evolution to WAC and the basic principles for affinity measurements. Preparation of columns for the immobilization of soluble target proteins and the development of lipodiscs for the incorporation of membrane proteins are described. The authors also discuss the advantages and limitations of WAC and compare it with other established techniques. Expert opinion: Although WAC is a suitable technique for fragment screening, with increased throughput, in particular, if coupled to mass spectrometry, it has not yet found the widespread application it deserves. A limiting factor may be the necessity for in house column preparation. In the future, the potential commercialization of columns with some important soluble protein targets would facilitate the application of WAC. The immobilization of membrane proteins on lipodisks is an area for further investigation, as is the comparison of WAC with other established methods since relevant information is still at a low level.
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Chromatography, Affinity/methods , Drug Discovery/methods , Small Molecule Libraries , Humans , Mass Spectrometry/methodsABSTRACT
AIMS: Glycogen synthase kinase 3 beta (GSK3ß) link with the mitochondrial Permeability Transition Pore (mPTP) in cardioprotection is debated. We investigated the role of GSK3ß in ischaemia (I)/reperfusion (R) injury using pharmacological tools. METHODS AND RESULTS: Infarct size using the GSK3ß inhibitor BIO (6-bromoindirubin-3'-oxime) and several novel analogues (MLS2776-MLS2779) was determined in anaesthetized rabbits and mice. In myocardial tissue GSK3ß inhibition and the specificity of the compounds was tested. The mechanism of protection focused on autophagy-related proteins. GSK3ß localization was determined in subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) isolated from Langendorff-perfused murine hearts (30'I/10'R or normoxic conditions). Calcium retention capacity (CRC) was determined in mitochondria after administration of the inhibitors in mice and in vitro. The effects of the inhibitors on mitochondrial respiration, reactive oxygen species (ROS) formation, ATP production, or hydrolysis were measured in SSM at baseline. Cyclosporine A (CsA) was co-administered with the inhibitors to address putative additive cardioprotective effects. Rabbits and mice treated with MLS compounds had smaller infarct size compared with control. In rabbits, MLS2776 and MLS2778 possessed greater infarct-sparing effects than BIO. GSK3ß inhibition was confirmed at the 10th min and 2 h of reperfusion, while up-regulation of autophagy-related proteins was evident at late reperfusion. The mitochondrial amount of GSK3ß was similar in normoxic SSM and IFM and was not altered by I/R. The inhibitors did not affect CRC or respiration, ROS and ATP production/hydrolysis at baseline. The co-administration of CsA ensured that cardioprotection was CypD-independent. CONCLUSION: Pharmacological inhibition of GSK3ß attenuates infarct size beyond mPTP inhibition.
Subject(s)
Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Mitochondria, Heart/drug effects , Myocardial Infarction/prevention & control , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/drug effects , Protein Kinase Inhibitors/pharmacology , Animals , Autophagy-Related Proteins/metabolism , Peptidyl-Prolyl Isomerase F/genetics , Peptidyl-Prolyl Isomerase F/metabolism , Disease Models, Animal , Female , Glycogen Synthase Kinase 3 beta/metabolism , Isolated Heart Preparation , Male , Mice, Inbred C57BL , Mice, Knockout , Mitochondria, Heart/enzymology , Mitochondria, Heart/pathology , Mitochondrial Membrane Transport Proteins/drug effects , Mitochondrial Membrane Transport Proteins/metabolism , Mitochondrial Permeability Transition Pore , Molecular Structure , Myocardial Infarction/enzymology , Myocardial Infarction/pathology , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/pathology , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Protein Kinase Inhibitors/chemistry , Rabbits , Signal Transduction , Structure-Activity RelationshipABSTRACT
The potential of Immobilized Artificial Membrane (IAM) chromatography to predict ecotoxicological endpoints of pesticides was investigated. For this purpose, retention factors of 39 structurally-diverse pesticides were measured on an IAM stationary phase. A representative test set of 6 pesticides was carefully selected. The training set, involving the remaining pesticides for which experimental data were available, served to establish linear IAM models with LC50/EC50 values in a series of aquatic organisms involving Rainbow Trout, Fathead Minnow, Bluegill Sunfish, Sheepshead Minnow, Eastern Oyster and Water Flea as well as LD50 values in honey bee, compiled from literature sources. For reasons of comparison, corresponding models were derived by replacing IAM retention factors with octanol-water partition coefficients (logP). Considering the similar regression equations obtained for the 4 fish species, general models to predict toxicity in fish were established. Most models were improved upon inclusion of additional physicochemical parameters. The positive contribution of Molecular Weight to ecotoxicity along with the positive sign of hydrogen bond indices in most cases implies that toxic action is manifested mainly by accumulation on the membrane rather than through diffusion across them. IAM models are generally followed by better statistics and superior predictive performance than those based on experimental or computed logP. Predictions based on IAM chromatography were comparable or even superior with those performed by EPI Suite Software. Hence, IAM retention factors are suggested as promising indices in order to screen or rank chemicals with respect to their ecotoxicological risk, especially in the case of new entities.
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Chromatography , Membranes, Artificial , Pesticides/toxicity , Animals , Aquatic Organisms/drug effects , Bees , Ecotoxicology/methods , Fishes , Models, Biological , Molecular WeightABSTRACT
INTRODUCTION: The complexity in the drug discovery pipeline, in combination with the exponential growth of experimental and computational data, the technological achievements, and the access to large data sets, has led to a continuous evolution and transformation of quantitative structure-activity relationships (QSAR) to compete with the challenges of multi-objective drug discovery. Areas covered: After a short overview of the multiple objectives involved in drug discovery, this review focuses on definition of the drug-like space and the construction of local and/or global models, platforms and workflows for step-by-step single-objective optimization (SOO) of the different and often conflicting processes. Multi-targeted drug design is a particular case of multi-objective QSAR integrated into the new era of polypharmacology. Multi-objective optimization (MOO), based on desirability functions or Pareto surfaces and its application in QSAR, as an alternative optimization philosophy, is also discussed. Expert opinion: Access to large databases as well as to software services by means of cloud technology facilitates research for more efficient and safer drugs. QSAR models implemented in web platforms and workflows provide sequential SOO for multiple biological and toxicity end points, while MOO, still restricted to a limited number of objectives, is helpful for multi-target or selectivity design, as well as for model prioritization.
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Drug Design , Drug Discovery/methods , Models, Theoretical , Cloud Computing , Databases, Factual , Humans , Molecular Targeted Therapy , Polypharmacology , Quantitative Structure-Activity RelationshipABSTRACT
Lipophilicity constitutes a vital physicochemical property in drug design as it is connected with pharmacodynamic and pharmacokinetic properties as well as toxicological aspects of candidate drugs. Traditional partitioning experiments to determine n-octanol-water coefficients are laborious and time-consuming, while they cannot be reliably performed for highly lipophilic or compounds undergoing degradation. Alternatively, lipophilicity of candidate drugs can be accurately and reproducibly determined using reversed-phase liquid chromatography. In this chapter, the details of protocols for lipophilicity assessment using reversed-phase HPLC, under conditions which provide the best simulation of n-octanol-water partition coefficients, are described.
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Drug Design , Drug Discovery/methods , 1-Octanol/chemistry , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Chromatography, Reverse-Phase/instrumentation , Chromatography, Reverse-Phase/methods , Drug Discovery/instrumentation , Humans , Water/chemistryABSTRACT
The aim of the study was to investigate the immobilized artificial membrane (IAM) retention mechanism for a set of flavonoids and to evaluate the potential of IAM chromatography to model Caco-2 permeability. For this purpose, the retention behavior of 41 flavonoid analogs on two IAM stationary phases, IAM.PC.MG and IAM.PC.DD2, was investigated. Correlations between retention factors, logkw(IAM) and octanol-water partitioning (logP) were established and the role of hydroxyl groups of flavonoids to the underlying retention mechanism was explored. IAM retention and logP values were used to establish sound linear models with Caco-2 permeability (logPapp ) taken from the literature. Both stepwise regression and multivariate analysis confirmed the contribution of hydrogen bond descriptors, as additional parameters in the either logkw(IAM) or logP models. Retention factors on both IAM stationary phases showed comparable performance with n-octanol-water partitioning towards Caco-2 permeability.
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Flavonoids/analysis , Intestinal Absorption/physiology , Membranes, Artificial , Models, Biological , Caco-2 Cells , Chromatography, Liquid , Flavonoids/chemistry , Flavonoids/metabolism , Humans , Hydrophobic and Hydrophilic InteractionsABSTRACT
The 46th EuroCongress on Drug Synthesis and Analysis (ECDSA-2017) was arranged within the celebration of the 65th Anniversary of the Faculty of Pharmacy at Comenius University in Bratislava, Slovakia from 5-8 September 2017 to get together specialists in medicinal chemistry, organic synthesis, pharmaceutical analysis, screening of bioactive compounds, pharmacology and drug formulations; promote the exchange of scientific results, methods and ideas; and encourage cooperation between researchers from all over the world. The topic of the conference, "Drug Synthesis and Analysis," meant that the symposium welcomed all pharmacists and/or researchers (chemists, analysts, biologists) and students interested in scientific work dealing with investigations of biologically active compounds as potential drugs. The authors of this manuscript were plenary speakers and other participants of the symposium and members of their research teams. The following summary highlights the major points/topics of the meeting.
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Drug Compounding , Chemistry, Pharmaceutical , Humans , Intersectoral Collaboration , Pharmacists , Quantitative Structure-Activity Relationship , Research Personnel , SlovakiaABSTRACT
INTRODUCTION: Lipophilicity, expressed as the octanol-water partition coefficient, constitutes the most important property in drug action, influencing both pharmacokinetic and pharmacodynamics processes as well as drug toxicity. On the other hand, biomimetic properties defined as the retention outcome on HPLC columns containing a biological relevant agent, provide a considerable advance for rapid experimental - based estimation of ADME properties in early drug discovery stages. Areas covered: This review highlights the paramount importance of lipophilicity in almost all aspects of drug action and safety. It outlines problems brought about by high lipophilicity and provides an overview of the drug-like metrics which incorporate lower limits or ranges of logP. The fundamental factors governing lipophilicity are compared to those involved in phospholipophilicity, assessed by Immobilized Artificial Membrane Chromatography (IAM). Finally, the contribution of biomimetic properties to assess plasma protein binding is evaluated. Expert opinion: Lipophilicity and biomimetic properties have important distinct and overlapping roles in supporting the drug discovery process. Lipophilicity is unique in early drug design for library screening and for the identification of the most promising compounds to start with, while biomimetic properties are useful for the experimentally-based evaluation of ADME properties for the synthesized novel compounds, supporting the prioritization of drug candidates and guiding further synthesis.
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Biomimetics/methods , Drug Discovery/methods , Pharmaceutical Preparations/chemistry , Chromatography/methods , Chromatography, High Pressure Liquid , Drug Design , Humans , Octanols/chemistry , Pharmaceutical Preparations/metabolism , Pharmacokinetics , Protein Binding , Water/chemistryABSTRACT
The potential of immobilized artificial membrane chromatography (IAM) to predict bioconcentration factors (BCF) of pharmaceutical compounds in aquatic organisms was studied. For this purpose, retention factors extrapolated to pure aqueous phase, logkw(IAM), of 27 drugs were measured on an IAM stationary phase, IAM.PC.MG type. The data were combined with retention factors on two IAM columns, IAM.PC.MG and IAM.PC.DD2 types, reported previously by our research group and correlated with logBCF values predicted by Estimation Program Interface (EPI Suite) Software. Linear models were established upon exclusion of ionic or highly hydrophilic nonionic drugs, for which a constant value of logBCF equal to 0.50 was arbitrarily assigned by EPI Suite Software. As additional physicochemical parameter BioWin5 proved to be statistically significant, expressing the decrease of bioaccumulation potential as a result of biodegradation in the aquatic environment. The constructed IAM model was successfully validated by application to a set of pharmaceuticals, whose experimental BCF values are available. Better predictions compared to EPI Suite Software were achieved for the dataset under study. Since bioconcentration process involves electrostatic interactions, IAM retention may be a better measure for BCF values, especially for ionic species, compared to octanol-water partition coefficients widely implemented in environmental sciences. The developed approach can be considered as a novel tool for the prediction of bioconcentration of pharmaceutical compounds in aquatic organisms in order to minimize further experimental assays in the future.
Subject(s)
Aquatic Organisms/metabolism , Chromatography, High Pressure Liquid , Membranes, Artificial , Pharmaceutical Preparations/chemistry , Pharmacokinetics , Biodegradation, Environmental , Chromatography, High Pressure Liquid/methods , Forecasting/methods , Linear Models , Tissue Distribution , WaterABSTRACT
OBJECTIVES: The transfer of xenobiotic compounds into human breast milk has raised serious concerns in the last few years. The present study is aimed to assess whether simple physicochemical properties exert significant impact on human breast milk transfer of drugs and chemicals. METHODS: A large data set of 375 xenobiotic compounds with available experimental milk to plasma (M/P) ratios was systematically compiled from the literature and explored with their physicochemical properties being further analyzed with respect to their extent to transfer into breast milk. RESULTS: Xenobiotic compounds with increased breast milk transfer (M/P ≥ 1) were characterized by enhanced lipophilicity and decreased molecular size (p < 0.05). Enhanced polarity and hydrogen bonding capacity were more frequently observed in xenobiotic compounds with reduced breast milk transfer (p < 0.0001). Xenobiotic compounds presenting increased positive charge at pH 7.4 were characterized by enhanced breast milk transfer (p < 0.001). Xenobiotic compounds presenting increased negative charge at pH 7.4 were characterized by decreased breast milk transfer (p < 0.001). CONCLUSIONS: The present study supports evidence that simple physicochemical properties related with lipophilicity, polarity, molecular size and ionization status exert significant impact on drugs and chemicals transport into human breast milk.
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INTRODUCTION: The development of immobilized artificial membrane (IAM) chromatography has unfolded new perspectives for the use of chromatographic techniques in drug discovery, combining simulation of the environment of cell membranes with rapid measurements. AREAS COVERED: The present review describes the characteristics of phosphatidylcholine-based stationary phases and analyses the molecular factors governing IAM retention in comparison to n-octanol-water and liposomes partitioning systems as well as to reversed phase chromatography. Other biomimetic stationary phases are also briefly discussed. The potential of IAM chromatography to model permeability through the main physiological barriers and drug membrane interactions is outlined. Further applications to calculate complex pharmacokinetic properties, related to tissue binding, and to screen drug candidates for phospholipidosis, as well as to estimate cell accumulation/retention are surveyed. EXPERT OPINION: The ambivalent nature of IAM chromatography, as a border case between passive diffusion and binding, defines its multiple potential applications. However, despite its successful performance in many permeability and drug-membrane interactions studies, IAM chromatography is still used as a supportive and not a stand-alone technique. Further studies looking at IAM chromatography in different biological processes are still required if this technique is to have a more focused and consistent application in drug discovery.
Subject(s)
Drug Discovery , Membranes, Artificial , Animals , Chromatography/methods , Humans , LiposomesABSTRACT
The potential of immobilized artificial membrane (IAM) chromatography to estimate human oral absorption (%HOA) was investigated. For this purpose, retention indices on IAM stationary phases reported previously by our group or measured by other authors under similar conditions were used to model %HOA data, compiled from literature sources. Considering the pH gradient in gastrointestinal tract, the highest logkw(IAM) values were considered, obtained either at pH7.4 or 5.5, defined as logkw(IAM)(best). Non linear models were established upon introduction of additional parameters and after exclusion of drugs which are substrates either to efflux or uptake transporters. The best model included Abraham's hydrogen-bond acidity parameter, molecular weight as well as the positively and negatively charged molecular fractions. For reasons of comparison between IAM chromatography and traditional lipophilicity, corresponding models were derived by replacing IAM retention factors with octanol-water distribution coefficients (logD). An overexpression of electrostatic interactions with phosphate anions was observed in the case of IAM retention as expressed by the negative contribution of the positively charged fraction F(+). The same parameter is statistically significant also in the logD model, but with a positive sign, indicating the attraction of basic drugs in the negatively charged inner membrane. To validate the obtained models a blind test set of 22 structurally diverse drugs was used, whose logkw(IAM)(best) values were determined and analyzed in the present study under similar conditions. IAM retention factors were further compared with MDCK cell lines permeability data taken from literature for a set of validation drugs. The overexpression of electrostatic interactions with phosphate anions on IAM surface was also evident in respect to MDCK permeability. In contrast to the clear classification between drugs with high and poor (or intermediate) absorption provided by MDCK permeability, %HOA plotted versus both IAM and logD data result in a saturation curve with a smoother ascending line.