A TiO₂@MWCNTs-based dispersive solid-phase extraction method for mitigating matrix effects in plasma LC-MS/MS...

The matrix effect is a prevalent interference in LC-MS/MS bioanalysis of small-molecule drugs, with lipids as a major source of such interference in plasma matrices. Leveraging the lipid-adsorbing capability of multi-walled carbon nanotubes (MWCNTs), this study synthesized TiO₂@MWCNTs composites and developed a novel dispersive solid-phase extraction (d-SPE) method to reduce matrix effects in rat plasma. Lipid profiles were compared to characterize the lipid purification capacity of TiO₂@MWCNTs in rat plasma samples. The matrix effects of representative small-molecule drugs, including metformin, amisulpride, and aripiprazole, were compared across TiO₂@MWCNTs-based d-SPE, protein precipitation, and traditional solid-phase extraction. Method validation and sample determination were subsequently performed. The results demonstrated that TiO₂ could be successfully loaded onto MWCNTs. The responses of 72 differential lipid ions were significantly reduced by at least 2-fold after TiO₂@MWCNTs treatment, and the IS-normalized matrix factors for metformin (from 13.69-20.00% to 31.49-44.39%) and amisulpride (from 71.01-84.82% to 91.69-101.48%) as well as the accuracy for aripiprazole at low concentration were significantly improved compared with protein precipitation treatment. Method validation results confirmed excellent selectivity, accuracy, precision, and reproducibility. The validated method was also successfully applied to a pharmacokinetic study of metformin with pharmacokinetic parameters comparable to those reported previously. This study shows that the dispersive solid-phase extraction method based on TiO₂@MWCNTs could act as a simple, rapid, low-cost and reliable pretreatment strategy to mitigate matrix effects for small-molecule analytes with low lgP in rat plasma as a proof-of-concept attempt.