Development and validation of an LC-MS/MS method for the determination of quetiapine and four related metabolites in human plasma

Pharmacokinetic measurement of the psychotropic compound quetiapine and four related metabolites in human plasma was conducted using a sensitive and specific liquid-chromatography tandem mass spectrometry (LC-MS/MS) assay that has been developed and validated for this purpose. The assay employs a single liquid-liquid extraction of quetiapine and its N-desalkyl (norquetiapine, M211,803, M1), 7-hydroxy (M214,227, M2),7-hydroxy N-desalkyl (M236,303, M3), and sulfoxide (M213,841, M4) metabolites from human plasma, and utilizes dual-column separation, using Luna C-18 columns (50 mm x 2.0 mm, 5 mu m) and positive ionization tandem MS detection in the multiple reaction monitoring (MRM) mode of the analytes and their respective stable labeled internal standards. The method provides a linear response from a quantitation range of < 0.70 ng/ml to at least 500 ng/ml for each analyte using 40 mu l of plasma. The applicable range was extended by dilution up to 100-fold with blank matrix. The accuracy and precision for quetiapine were less than 6.0% and 6.4% for quetiapine, respectively. The accuracy (and precision) was less than 9.4% (5.9%) for norquetiapine; 6.4% (6.2%) for M2; and 10.0% (6.4%) for M3; and 8.6% (9.5%) for M4. This methodology enabled the determination of the pharmacokinetics of quetiapine and its metabolites in human plasma, and an example of its application is presented. (C) 2009 Elsevier B.V. All rights reserved.