Development of polyanion-metal ion solution systems to overcome phospholipids-related matrix effects in...

Phospholipids-related matrix effects are a major source impacting the reproducibility of analyte quantification in LC-MS/MS-based bioanalysis. This study intended to evaluate different combinations of polyanion-metal ion based solution system for phospholipids removal and elimination of matrix effects in human plasma. Blank plasma samples or plasma samples spiked with model analytes were proceeded with different combinations of polyanions (dextran sulfate sodium (DSS) and alkalized colloidal silica (Ludox)) and metal ions (MnCl₂, LaCl₃, and ZrOCl₂) followed with acetonitrile-based protein precipitation. The representative classes of phospholipids and model analytes (acid, neutral, and base) were detected using multiple reaction monitoring mode. The polyanion-metal ion systems were explored for providing balanced analyte recovery and phospholipids removal by optimizing reagent concentrations or adding formic acid and citric acid as the shielding modifiers. The optimized polyanion-metal ion systems were further evaluated for eliminating matrix effects of non-polar and polar compounds. Any combinations of polyanions (DSS and Ludox) and metal ions (LaCl₃ and ZrOCl₂) could completely remove phospholipids at best-case scenario, while the analyte recovery is low for compounds with special chelation groups. Addition of formic acid or citric acid can improve analyte recovery but significantly decrease the removal efficiency of phospholipids. Optimized ZrOCl₂-Ludox/DSS systems provided efficient phospholipids removal (>85%) and adequate analyte recovery, and the systems also correctly eliminated ion suppression or enhancement of the non-polar and polar drugs. The developed ZrOCl₂-Ludox/DSS systems are cost-effective and versatile for balanced phospholipids removal and analyte recovery and provide adequate elimination of matrix effects.