Analysis and pharmacokinetics of quetiapine and two metabolites in human plasma using reversed-phase HPLC with ultraviolet and electrochemical detection

Abstract

A sensitive and specific HPLC assay for the measurement of the antipsychotic compound quetiapine in human plasma has been developed and validated. The assay employs a three-step liquid–liquid extraction of quetiapine and its 7-hydroxylated and 7-hydroxylated, N-dealkylated metabolites from human plasma, and utilizes ultraviolet (UV) detection of quetiapine and electrochemical detection of the metabolites. The method provides a linear response from a quantitation limit of 2.50 to 500 ng ml −1 for each analyte using 0.4 ml plasma. The assay is applicable from 500 to 5000 ng ml −1 by sample dilution with de-ionized water. The inter-assay precision of quetiapine in plasma calibration standards across 4 validation days averaged 11.9% relative standard deviation (RSD) over the range 2.50 to 500 ng ml −1, with intra-assay precision averaging 16.0% RSD and mean accuracy of 98.6% of theory. Similarly, the inter-assay precision of the 7-hydroxylated metabolite in plasma calibration standards across 4 validation days averaged 13.7% RSD over the range 2.50 to 500 ng ml −1, with intra-assay precision averaging 17.6% RSD and mean accuracy of 109% of theory. The 7-hydroxylated, N-dealkylated metabolite demonstrated inter-assay precision of 16.2% RSD, intra-assay precision of 19.9% RSD, and mean accuracy of 104% of theory over the range 2.50 to 500 ng ml −1. The present assay method was used to support a study comparing the pharmacokinetic profile of quetiapine with the time course of dopamine D 2 and serotinin 5-HT 2 receptor occupancy in the brain using positron emission tomography (PET). We describe in this paper the bioanalytical method and the plasma concentrations of quetiapine and its metabolites resulting from this study.