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Loidl-Stahlhofen, Angelika; Hartmann, Thorsten; Schöttner, Matthias; Röhring, Cornelia; Brodowsky, Hanna M.; Schmitt, Johannes; Keldenich, Jörg

doi:10.1023/a:1013343117979

Cited by 70 publications

(52 citation statements)

References 20 publications

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“…com/what-we-do/databaseforms.aspx?id = 385), R 2 only increases to 0.45. A highlight of recent drug-lipid association studies is the high-throughput lipid partition study of 186 compounds by Loidl-Stahlhofen et al, [11] who found similar results: R 2 = 0.54 for K p,vol vs. log D in the case of neutral drugs, and R 2 = 0.24 for acidic/basic drugs. (In this study lipid and drug concentrations were also selected so as to keep X D < 0.01.)…”

Section: A C H T U N G T R E N N U N G Binding Of Drugsmentioning

confidence: 86%

“…The problem is that determining the partition coefficient is usually relatively time consuming, although high-throughput methods are emerging. [11] Instead of aiming at the exact partition coefficient, our approach was to use an existing high-throughput system that would allow the screening of 10 000-15 000 drugs per year, though at the cost of less exact, more vague, and more error-prone interaction parameters for the drugs and the anionic lipids. [208] The interaction parameter used was the relative drug-induced decrease in the critical micelle concentration (CMC) of a short-chain anionic phosphatidylserine.…”

Section: Drug-phospholipid Interaction Screeningmentioning

confidence: 99%

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Screening for the Drug–Phospholipid Interaction: Correlation to Phospholipidosis

2009

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Phospholipid bilayers represent a complex, anisotropic environment fundamentally different from bulk oil or octanol, for instance. Even "simple" drug association to phospholipid bilayers can only be fully understood if the slab-of-hydrocarbon approach is abandoned and the complex, anisotropic properties of lipid bilayers reflecting the chemical structures and organization of the constituent phospholipids are considered. The interactions of drugs with phospholipids are important in various processes, such as drug absorption, tissue distribution, and subcellular distribution. In addition, drug-lipid interactions may lead to changes in lipid-dependent protein activities, and further, to functional and morphological changes in cells, a prominent example being the phospholipidosis (PLD) induced by cationic amphiphilic drugs. Herein we briefly review drug-lipid interactions in general and the significance of these interactions in PLD in particular. We also focus on a potential causal connection between drug-induced PLD and steatohepatitis, which is induced by some cationic amphiphilic drugs.

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Section: A C H T U N G T R E N N U N G Binding Of Drugsmentioning

confidence: 86%

Section: Drug-phospholipid Interaction Screeningmentioning

confidence: 99%

Screening for the Drug–Phospholipid Interaction: Correlation to Phospholipidosis

2009

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“…In the latter, a broader range of lipid concentrations is used, improving the precision of the measurement [135]. It has been shown that the lipid composition of TRANSIL ® spheres can be easily modified which enables different barriers the drug must cross in vivo to be mimicked, for example, by introduction of negatively charged phosphatidylserine (PS) for drugs designed to pass through the blood-brain barrier which is rich in negatively charged compounds [136].…”

Section: Examples Of Particulate Systems For Hts Applications the Detmentioning

confidence: 99%

“…The other type of experimental models are based on nano-particles [23][24][25][26][27]. Some methods need an independent determination of the compound concentration which in large scale screening might cause substantial difficulty [24,[27][28][29]. Concentrations are determined directly using standard analytical methods or by evaluating the amount of the probe frequently used for labeling of the compound [30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

Application of Liposome Based Sensors in High-Throughput Screening Systems

Przybyło¹,

Borowik²,

Langner

2007

CCHTS

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High throughout screening is an approach based on the concept which assumes that when sufficiently large library of compounds are tested, the chance of discovering a new active compound is increased. In order to meet this expectation, proper testing criteria need to be devised. Those criteria should be related to the fate of a compound in the organism to have any predictive power. Not long ago, the main criteria were based exclusively on parameters defined by the maximum activity (QSAR). In this system the activity criteria have not been included therefore the compound ability to reach the target is not accounted for. Considering that, the construction of yet another set of parameters has been initiated (QSPR). The parameters are in fact semi-empirical numbers which need to be tested on real, physical models. Whereas the activity tests are straightforward, the pharmacokinetic ones are difficult and controversial. One such parameter describes the critical property of an active compound, namely its ability to cross biological membranes. This review describes new concepts in the determination of the permeability coefficient with the help of methods which are based on liposome biosensors. Two methods using fluorescence probes incorporated in the lipid bilayer of liposome are described in detail and compared to other currently available techniques.

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“…moleculardevices.com). A further description of the materials and the detailed calculation of membrane affinity or serum protein binding is described in [3], [4] and [5].…”

Section: Introductionmentioning

confidence: 99%

ADME Related Profiling in 96 and 384 Well Plate Format - A Novel and Robust HT-Assay for the Determination of Lipophilicity and Serum Albumin Binding

Hartmann¹,

Schmitt²,

Röhring³

et al. 2006

CDD

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The failure of about half of the drug candidates is associated with poor pharmacokinetic properties leading to a huge loss of time and money [1]. Early profiling of drug like properties provides important information in order to screen out insoluble, poorly absorbed and toxic compounds. Today, large compound libraries have to be screened, and of course the total number of compounds will rise over the next years leading to a growing demand for fully automated assays. A balance between quality, speed, throughput, cost and information content can be accomplished by the careful selection of assays and experimental conditions. Here we describe a novel 384 well format assay for two important ADME related descriptors (lipophilicity and serum protein binding) as input parameters for a precise prediction of fraction absorbed, blood/organ distribution coefficients and permeability, in order to maximize the information about a compound at an early stage of discovery.

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Abstract: Solid-supported lipid membranes represent a valuable tool to determine physiologically relevant lipid-water partitioning data of pharmaceuticals in an automated setup and is well suited for high-throughput data generation in lead optimization programs.

Cited by 70 publications

References 20 publications

Screening for the Drug–Phospholipid Interaction: Correlation to Phospholipidosis

Screening for the Drug–Phospholipid Interaction: Correlation to Phospholipidosis

Application of Liposome Based Sensors in High-Throughput Screening Systems

ADME Related Profiling in 96 and 384 Well Plate Format - A Novel and Robust HT-Assay for the Determination of Lipophilicity and Serum Albumin Binding

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