Development of Sensitive and High-Throughput Liquid Chromatography-Tandem Mass Spectrometry Method for Quantification of Haloperidol in Human Plasma with Phospholipid Removal Pretreatment

Haloperidol, butyrophenone derivative, is a typical antipsychotic drug used in the treatment of schizophrenia, manic phase of bipolar disorder, and acute psychomotor agitations. According to the recent guidelines for therapeutic drug monitoring, it is strongly recommended to measure plasma level during the therapy with haloperidol. The objective of this study was to develop and validate a simple liquid chromatography-tandem mass spectrometry-based method to quantitate haloperidol in human plasma. After one-step extraction procedure using OSTRO (TM) plate, gradient elution on Acquity UPLC BEH C18 (50x2.1mm, 1.7 mu m) column over 3.2 min was performed. The detection was conducted on a triple quadrupole tandem mass spectrometer by multiple reaction monitoring mode in positive ionization mode with transitions at m/z 376.29 -> 165.14 and m/z 380.28 -> 169.17 for haloperidol and haloperidol-d(4) (used as an internal standard), respectively. The method was fully validated to cover wide concentration range of 0.05-80 ng/mL in human plasma and meets the criteria for the selectivity, linearity and lower limit of detection, precision and accuracy, matrix effect, extraction recovery, carryover, dilution integrity and stability. The extraction recovery was nearly 100%, and no significant matrix effects were observed. Therefore, the method is applicable to routine therapeutic drug monitoring in patients' plasma.