scholarly journals Revisiting the application of Immobilized Artificial Membrane (IAM) chromatography to estimate in vivo distribution properties of drug discovery compounds based on the model of marketed drugs

ADMET & DMPK ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 78-97
Author(s):  
Klara Livia Valko ◽  
Silvia Rava ◽  
Shenaz Bunally ◽  
Scott Anderson
Keyword(s):  
Drug Discovery ◽  
Volume Of Distribution ◽  
Artificial Membrane ◽  
Distribution Models ◽  
In Vivo Distribution ◽  
Drug Molecules ◽  
Column System ◽  
Immobilized Artificial Membrane ◽  
Drug Efficiency

Immobilized Artificial Membrane (IAM) chromatography columns have been used to model the in vivo distribution of drug discovery compounds. Regis Technologies Inc., the manufacturer, had to replace the silica support and consequently introduced a new IAM.PC.DD2 column that shows slightly different selectivity towards acidic and basic compounds. The application of the new IAM.PC.DD2 columns has been evaluated and the in vivo distribution models have been compared with the previous batches of columns. It was found that due to the improved endcapping of the silica, some of the positively charged drug molecules showed shorter retention than previously published. Therefore, the column system suitability data have been updated. However, these differences do not significantly affect the previously published models for the volume of distribution, brain tissue binding and drug efficiency. Therefore, the published models can be used with the new IAM.PC.DD2 columns.

scholarly journals In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

ADMET & DMPK ◽  
2017 ◽  
Vol 5 (1) ◽  
pp. 14 ◽  
Author(s):  
Klara Livia Valko ◽  
Simon P. Teague ◽  
Charles Pidgeon
Keyword(s):  
Drug Discovery ◽  
Protein Binding ◽  
Specific Binding ◽  
Efficiency Index ◽  
Log P ◽  
Basic Principles ◽  
In Vivo Distribution ◽  
Drug Efficiency

<p class="ADMETabstracttext">The drug discovery process can be accelerated by chromatographic profiling of the analogs to model in vivo distribution and the major non-specific binding. A balanced potency and chromatographically determined membrane and protein binding (IAM MB/PB) data enable selecting drug discovery compounds for further analysis that have the highest probability to show the desired in vivo distribution behavior for efficacy and reduced chance for toxicity. Although the basic principles of the technology have already appeared in numerous publications, the lack of standardized procedures limited its widespread applications especially in academia and small drug discovery biotech companies. In this paper, the standardized procedures are described that has been trademarked as Regis IAM MB/PB Technology®. Comparison between the Drug Efficiency Index (DEI=pIC50-logVdu+2) and generally used Ligand Lipophilicity Efficiency (LLE) has been made, demonstrating the advantage of measured IAM and HSA binding over calculated log P. The power of the proposed chromatographic technology is demonstrated using the data of marketed drugs.</p>

scholarly journals Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents

2014 ◽  
Vol 70 (3) ◽  
pp. 857-867 ◽  
Author(s):  
Suresh B. Lakshminarayana ◽  
Tan Bee Huat ◽  
Paul C. Ho ◽  
Ujjini H. Manjunatha ◽  
Véronique Dartois ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Volume Of Distribution ◽  
Metabolic Stability ◽  
New Drugs ◽  
Pharmacokinetic Parameters ◽  
Lipinski’S Rule ◽  
Drug Classes ◽  
Human Pharmacokinetic

Abstract Objectives The discovery and development of TB drugs has met limited success, with two new drugs approved over the last 40 years. Part of the difficulty resides in the lack of well-established in vitro or in vivo targets of potency and physicochemical and pharmacokinetic parameters. In an attempt to benchmark and compare such properties for anti-TB agents, we have experimentally determined and compiled these parameters for 36 anti-TB compounds, using standardized and centralized assays, thus ensuring direct comparability across drugs and drug classes. Methods Potency parameters included growth inhibition, cidal activity against growing and non-growing bacteria and activity against intracellular mycobacteria. Pharmacokinetic parameters included basic physicochemical properties, solubility, permeability and metabolic stability. We then attempted to establish correlations between physicochemical, in vitro and in vivo pharmacokinetic and pharmacodynamic indices to tentatively inform future drug discovery efforts. Results Two-thirds of the compounds tested showed bactericidal and intramacrophage activity. Most compounds exhibited favourable solubility, permeability and metabolic stability in standard in vitro pharmacokinetic assays. An analysis of human pharmacokinetic parameters revealed associations between lipophilicity and volume of distribution, clearance, plasma protein binding and oral bioavailability. Not surprisingly, most compounds with favourable pharmacokinetic properties complied with Lipinski's rule of five. Conclusions However, most attempts to detect in vitro–in vivo correlations were unsuccessful, emphasizing the challenges of anti-TB drug discovery. The objective of this work is to provide a reference dataset for the TB drug discovery community with a focus on comparative in vitro potency and pharmacokinetics.

scholarly journals Biomimetic properties and estimated in vivo distribution of chloroquine and hydroxy-chloroquine enantiomers

ADMET & DMPK ◽  
2021 ◽  
Author(s):  
Klara Livia Valko ◽  
Tong Zhang
Keyword(s):  
Large Volume ◽  
Volume Of Distribution ◽  
Tissue Binding ◽  
Binding Medium ◽  
Acid Glycoprotein ◽  
Phospholipid Binding ◽  
Racemic Mixtures ◽  
High Level ◽  
Drug Efficiency

Chloroquine and hydroxy-chloroquine already established as anti-malarial and lupus drugs have recently gained renewed attention in the fight against the Covid-19 pandemic. Bio-mimetic HPLC methods have been used to measure the protein and phospholipid binding of the racemic mixtures of the drugs. The tissue binding and volume of distribution of the enantiomers have been estimated. The enantiomers can be separated using Chiralpak AGP HPLC columns. From the α-1-acid-glycoprotein (AGP) binding, the lung tissue binding can be estimated for the enantiomers. The drugs have a large volume of distribution, showed strong and stereoselective glycoprotein binding, medium-strong phospholipid-binding indicating only moderate phospholipidotic potential, hERG inhibition and promiscuous binding. The drug efficiency of the compounds was estimated to be greater than 2 % which indicates a high level of free biophase concentration relative to dose. The biomimetic properties of the compounds support the well-known tolerability of the drugs.

scholarly journals Erratum to the paper: In vitro membrane binding and protein binding (IAM MB/PB technology) to estimate in vivo distribution: applications in early drug discovery

ADMET & DMPK ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 267-268
Author(s):  
Klara Livia Valko ◽  
Simon Teague ◽  
Charles Pudgeon
Keyword(s):  
Drug Discovery ◽  
Protein Binding ◽  
Membrane Binding ◽  
In Vivo Distribution ◽  
Early Drug

The authors of the original paper published with the same title: ADMET & DMPK 5(1) (2017) 14-38; doi: 10.5599/admet.5.1.373, apologize for the error in the plot on Figure 5. The erratum gives a correct plot.

scholarly journals Rapid Screening of Blood-Brain Barrier Penetration of Drugs Using the Immobilized Artificial Membrane Phosphatidylcholine Column Chromatography

2005 ◽  
Vol 11 (1) ◽  
pp. 13-20 ◽  
Author(s):  
Chi Ho Yoon ◽  
Soo Jin Kim ◽  
Beom Soo Shin ◽  
Kang Choon Lee ◽  
Sun Dong Yoo
Keyword(s):  
Blood Brain Barrier ◽  
Prediction Method ◽  
Brain Barrier ◽  
Rapid Screening ◽  
Artificial Membrane ◽  
Immobilized Artificial Membrane ◽  
Blood Brain ◽  
Cns Penetration

The chromatographic capacity factors (kIAM) of 23 structurally diverse drugs were measured by the immobilized artificial membrane (kIAM) phosphatidylcholine chromatography for the prediction of blood-brain barrier (BBB) penetration. The kIAM was determined using themobile phase consisting of acetonitrile:DPBS (20:80 v/v) and corrected for the molar volume of the solutes (kIAM/MWn). The correlation between kIAM/MWn and CNS penetration was highest when measured at pH 5.5 with the power function of n = 4. This in vitro predictionmethod was validated with 7 newly synthesized PDE-4 inhibitors. The relationship between in vivo plasma-to-brain concentration ratios and in vitro CNS penetration was excellent ( r= 0.959). The developed in vitro prediction method may be used as a rapid screening tool for BBB penetration of drugs with passive transport mechanism, with high success, low cost, and reproducibility.

Advances in immobilized artificial membrane (IAM) chromatography for novel drug discovery

2016 ◽  
Vol 11 (5) ◽  
pp. 473-488 ◽  
Author(s):  
Fotios Tsopelas ◽  
Theodosia Vallianatou ◽  
Anna Tsantili-Kakoulidou
Keyword(s):  
Drug Discovery ◽  
Artificial Membrane ◽  
Immobilized Artificial Membrane ◽  
Novel Drug
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