Abstract
Current advances of new technologies with robotic automated assays combined with highly selective and sensitive LC-MS enable high-speed screening of lead series libraries in many in vitro assays. In this review, we summarize state of the art high throughput assays for screening of key physicochemical properties such as solubility, lipophilicity, pKa, drug-plasma protein binding and brain tissue binding as well as in vitro ADME profiling. We discuss two primary approaches for high throughput screening of solubility, i.e. an automated 96-well plate assay integrated with LC-MS and a rapid multi-wavelength UV plate reader. We address the advantages of newly developed miniaturized techniques for high throughput pKa screening by capillary electrophoresis combined with mass spectrometry (CE-MS) with automated data analysis flow. Several new lipophilicity approaches other than octanol-water partitioning are critically reviewed, including rapid liquid chromatographic retention based approach, immobilized artificial membrane (IAM) partitioning and liposome, and potential microemulsion electrokinetic chromatography (MEEKC) for accurate screening of LogP. We highlight the sample pooling (namely cassette dosing, all-in-one, cocktail) as an efficient approach for high throughput screening of physicochemical properties and in vitro ADME profiling with emphasis on the benefit of on-line quality control. This cassette dosing approach has been widely adapted in drug discovery for rapid screening of in vivo pharmacokinetic parameters with significantly increased capacity and dramatically reduced animal usage.
Keywords: High throughput screening (HTS), sample pooling, cassette dosing, in vivo PK, physicochemical property, ADME, in vitro screening, LC-MS, drug discovery
Combinatorial Chemistry & High Throughput Screening
Title: High Throughput Screening of Physicochemical Properties and In Vitro ADME Profiling in Drug Discovery
Volume: 12 Issue: 3
Author(s): Hong Wan and Anders G. Holmen
Affiliation:
Keywords: High throughput screening (HTS), sample pooling, cassette dosing, in vivo PK, physicochemical property, ADME, in vitro screening, LC-MS, drug discovery
Abstract: Current advances of new technologies with robotic automated assays combined with highly selective and sensitive LC-MS enable high-speed screening of lead series libraries in many in vitro assays. In this review, we summarize state of the art high throughput assays for screening of key physicochemical properties such as solubility, lipophilicity, pKa, drug-plasma protein binding and brain tissue binding as well as in vitro ADME profiling. We discuss two primary approaches for high throughput screening of solubility, i.e. an automated 96-well plate assay integrated with LC-MS and a rapid multi-wavelength UV plate reader. We address the advantages of newly developed miniaturized techniques for high throughput pKa screening by capillary electrophoresis combined with mass spectrometry (CE-MS) with automated data analysis flow. Several new lipophilicity approaches other than octanol-water partitioning are critically reviewed, including rapid liquid chromatographic retention based approach, immobilized artificial membrane (IAM) partitioning and liposome, and potential microemulsion electrokinetic chromatography (MEEKC) for accurate screening of LogP. We highlight the sample pooling (namely cassette dosing, all-in-one, cocktail) as an efficient approach for high throughput screening of physicochemical properties and in vitro ADME profiling with emphasis on the benefit of on-line quality control. This cassette dosing approach has been widely adapted in drug discovery for rapid screening of in vivo pharmacokinetic parameters with significantly increased capacity and dramatically reduced animal usage.
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Cite this article as:
Wan Hong and Holmen G. Anders, High Throughput Screening of Physicochemical Properties and In Vitro ADME Profiling in Drug Discovery, Combinatorial Chemistry & High Throughput Screening 2009; 12 (3) . https://dx.doi.org/10.2174/138620709787581701
DOI https://dx.doi.org/10.2174/138620709787581701 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
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