采用反相高效液相色谱法结合紫外和电化学检测法对人血浆中喹硫平及其两种代谢物进行分析和药代动力学研究。

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

作者信息

Davis P C, Wong J, Gefvert O

机构信息

Drug Disposition and Metabolism Department, Zeneca Pharmaceuticals, Wilmington, DE 19850, USA.

出版信息

J Pharm Biomed Anal. 1999 Jun;20(1-2):271-82. doi: 10.1016/s0731-7085(99)00036-9.

DOI:10.1016/s0731-7085(99)00036-9

PMID:10704032

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 D2 and serotonin 5-HT2 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.

摘要

已开发并验证了一种灵敏且特异的HPLC分析法，用于测定人血浆中的抗精神病化合物喹硫平。该分析法采用三步液-液萃取法，从人血浆中提取喹硫平及其7-羟基化和7-羟基化、N-去烷基化代谢物，并利用喹硫平的紫外（UV）检测和代谢物的电化学检测。该方法使用0.4 ml血浆，对每种分析物在2.50至500 ng ml⁻¹的定量限范围内提供线性响应。通过用去离子水稀释样品，该分析法适用于500至5000 ng ml⁻¹的范围。在4个验证日内，血浆校准标准品中喹硫平的批间精密度在2.50至500 ng ml⁻¹范围内平均相对标准偏差（RSD）为11.9%，批内精密度平均RSD为16.0%，平均准确度为理论值的98.6%。同样，在4个验证日内，血浆校准标准品中7-羟基化代谢物的批间精密度在2.50至500 ng ml⁻¹范围内平均RSD为13.7%，批内精密度平均RSD为17.6%。平均准确度为理论值的109%。在2.50至500 ng ml⁻¹范围内，7-羟基化、N-去烷基化代谢物的批间精密度为16.2% RSD，批内精密度为19.9% RSD，平均准确度为理论值的104%。本分析方法用于支持一项研究，该研究使用正电子发射断层扫描（PET）比较喹硫平的药代动力学特征与大脑中多巴胺D2和5-羟色胺5-HT2受体占有率的时间进程。我们在本文中描述了生物分析方法以及该研究产生的喹硫平及其代谢物的血浆浓度。