Development and validation of a sensitive and robust LC-MS/MS with electrospray ionization method for simultaneous quantitation of quetiapine and its active metabolite norquetiapine in human plasma

Background: Quetiapine is an atypical antipsychotic agent for the treatment of schizophrenia, acute mania, and acute bipolar depression. The antidepressive response is considered to be mediated by the metabolite norquetiapine (N-desalkylquetiapine), and the aim of this study was to develop an LC-MS/MS method to measure concentrations of these compounds in human plasma. Methods: Following one step liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a Sunfire C18 column (50 mm x 2.1 mm, 5 pm). The retention times were 2.12, 224, 2.12 and 2.19 mm for quetiapine, norquetiapine and their respective stable labeled internal standards, respectively. Cycle time was 4 min.Selected reaction monitoring (SRM) in positive ion mode was used for quantitation. Results: The present method exhibited a linear dynamic range of 0.5-500 ng/ml for quetiapine and 0.6-600 ng/ml for norquetiapine. The applicable range was extended by dilution up to 5-fold with blank matrix. The accuracy and precision for quetiapine were <103.0% and 8.8%, for norquetiapine were <108.8% and 11.1%, respectively. Conclusions: A rapid, sensitive, and robust LC-MS/MS method for quantifying quetiapine and its metabolite norquetiapine levels in human plasma was validated and successfully applied to samples from schizophrenic patients in clinical pharmacokinetics studies. (C) 2013 Elsevier B.V. All rights reserved.