Compound Property Optimization in Drug Discovery Using Quantitative Surface Sampling Micro Liquid Chromatography with Tandem Mass Spectrometry

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• 作者：Xiaohui Chen ; Panos Hatsis ; Joyce Judge ; Upendra A. Argikar ; Xiaojun Ren ; Jason Sarber ; Keith Mansfield ; Guiqing Liang ; Adam Amaral ; Alexandre Catoire ; Adam Bentley ; Luis Ramos ; Paul Moench ; Samuel Hintermann ; David Carcache ; Jim Glick ; Jimmy Flarakos
• 刊名：Analytical Chemistry
• 出版年：2016
• 出版时间：December 6, 2016
• 年：2016
• 卷：88
• 期：23
• 页码：11813-11820
• 全文大小：343K
• ISSN：1520-6882

文摘

Surface sampling micro liquid chromatography tandem mass spectrometry (SSμLC-MS/MS) was explored as a quantitative tissue distribution technique for probing compound properties in drug discovery. A method was developed for creating standard curves using surrogate tissue sections from blank tissue homogenate spiked with compounds. The resulting standard curves showed good linearity and high sensitivity. The accuracy and precision of standards met acceptance criteria of ±30%. A new approach was proposed based on an experimental and mathematical method for tissue extraction efficiency evaluation by means of consecutively sampling a location on tissue twice by SSμLC-MS/MS. The observed extraction efficiency ranged from 69% to 82% with acceptable variation for the test compounds. Good agreement in extraction efficiency was observed between surrogate tissue sections and incurred tissue sections. This method was successfully applied to two case studies in which tissue distribution was instrumental in advancing project teams’ understanding of compound properties.