title: Compound Property Optimization in Drug Discovery Using Quantitative Surface Sampling Micro Liquid Chromatography with Tandem Mass Spectrometry.
abstract: 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.
authors: Xiaohui
authors: X
authors: Chen
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, Inc. 1 Health Plaza, East Hanover, New Jersey 07936 United States.
authors: Panos
authors: P
authors: Hatsis
authors: Joyce
authors: J
authors: Judge
authors: Upendra A
authors: UA
authors: Argikar
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, Inc. 1 Health Plaza, East Hanover, New Jersey 07936 United States.
authors: Xiaojun
authors: X
authors: Ren
authors: Jason
authors: J
authors: Sarber
authors: Keith
authors: K
authors: Mansfield
authors: Guiqing
authors: G
authors: Liang
authors: Adam
authors: A
authors: Amaral
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, Inc. 1 Health Plaza, East Hanover, New Jersey 07936 United States.
authors: Alexandre
authors: A
authors: Catoire
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, Inc. 1 Health Plaza, East Hanover, New Jersey 07936 United States.
authors: Adam
authors: A
authors: Bentley
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, Inc. 1 Health Plaza, East Hanover, New Jersey 07936 United States.
authors: Luis
authors: L
authors: Ramos
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, Inc. 1 Health Plaza, East Hanover, New Jersey 07936 United States.
authors: Paul
authors: P
authors: Moench
authors: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc. 4056 Basel, Switzerland.
authors: Samuel
authors: S
authors: Hintermann
authors: Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Inc. 4056 Basel, Switzerland.
authors: David
authors: D
authors: Carcache
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, Inc. 1 Health Plaza, East Hanover, New Jersey 07936 United States.
authors: Jim
authors: J
authors: Glick
authors: Drug Metabolism & Pharmacokinetics, Novartis Institutes for BioMedical Research, Inc. 1 Health Plaza, East Hanover, New Jersey 07936 United States.
authors: Jimmy
authors: J
authors: Flarakos
mesh_terms: D002853:Chromatography, Liquid / Q000295:instrumentation; D055808:Drug Discovery; D004364:Pharmaceutical Preparations / Q000032:analysis*; D013499:Surface Properties; D053719:Tandem Mass Spectrometry / Q000295:instrumentation
chemical_list: D004364:Pharmaceutical Preparations