Electromembrane extraction of chlorprothixene, haloperidol and risperidone from whole blood and urine
Introduction
Antipsychotics have been widely used for psychotic disorders such as schizophrenia, bipolar disorders, mania, hallucinations, dementia, and sleeping disorders [1], [2], [3]. Though the second-generation of antipsychotics show better efficacy and less side effects than the first-generation of antipsychotics, a number of researches confirmed that all antipsychotics may give rise to unpleasant side effects and severe poisoning after overdose [4], [5]. However, in order to boost the respective efficacy, many psychiatric patients were treated with more than one antipsychotic drug in their routine practices [2]. Thus, an accurate, sensitive, selective and reliable quantitative method to quantify antipsychotic drugs in biological fluids is of great importance and helpful for therapeutic drug monitoring (TDM), controlling the efficacy and safety of these drugs, as well as for forensic toxicology analysis [4], [6].
Chlorprothixene (CPX) and haloperidol (HAL) represent the first generation of antipsychotics, and risperidone (RIS) (Fig. 2) represents the second generation of antipsychotics [7], [8]. Many analytical techniques have been applied for the detection of antipsychotics in biological specimens such as human plasma, human urine, human organs and rat plasma [7], [8], [9], [10], [11], [12], [13]. Among them, due to the high selectivity and sensitivity, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become the mainstay for simultaneous determination of antipsychotics in complex biological matrix [14], [15]. However, biological specimens contain a lot of endogenous compounds such as proteins, acids and salts, which may lead to high background signal, ion suppression and sensitivity reduction of LC-MS/MS [16]. Hence, sample preparation is mandatory prior to the instrumental analysis. Classic sample preparation approached of liquid-liquid extraction (LLE) and solid-phase extraction (SPE) have been applied in sample preparation for extraction of pharmaceuticals. However, traditional LLE and SPE has shown some drawbacks such as requiring large amounts of sample and organic solvents, formation of emulsion and involving multiple operation steps [17]. Thus, miniaturized, simple, compatible with the analytical instruments and friendly to environment sample preparation techniques have caught increasing attention [17], [18].
Microextraction procedure based on solid-phase approaches for instance solid-phase microextraction (SPME) and microextraction by packed sorbent (MEPS) have been applied for extraction of antipsychotics [19], [20], [21]. By SPME-LC-MS/MS and MEPS coupled with gas chromatography–tandem mass spectrometry (GC-MS/MS), the limit of detection (LOD) of HAL from human plasma samples was 0.2 and 0.8 ng/mL, respectively [19], [20]. Another miniaturized sample preparation method, dispersive liquid-liquid microextraction has been applied for extracting antipsychotics [13], [22], though it displayed significant matrix effect when LC-MS/MS was utilized to analyze RIS [22]. Thus, an ideal sample preparation technique should also be with high sample clean-up capability [17]. Liquid-phase microextraction (LPME) which requires less organic solvent (usually a few microliter or even less) and with sufficient sample clean-up capability also has been used for the isolation of RIS [9]. In this work, RIS was extracted from human plasma by 60 min hollow fiber-LPME (HF-LPME) using 1-octanol as the supported liquid membrane (SLM), and the linear range (analyzed by capillary electrophoresis) was from 100-5000 ng mL−1. The mass transfer of LPME is controlled by the pH and concentration gradient, and the mass transfer rate depends on the diffusion rate of the analytes [18].
Electromembrane extraction (EME), which was inspired by LPME, was firstly introduced in 2006 by Pedersen-Bjergaard to accelerate the separation of non-polar basic drugs from biological fluids [23]. SLM, the key component in HF-LPME as well as in EME, is a water immiscible organic solvent impregnated in the porous membrane's pores. The SLM blocks the sample into the acceptor solution, prohibiting the transit of major matrix components, such as proteins, phospholipids and DNA. When the electric field is applied, the charged analytes in the sample can migrate across the SLM and finally trapped in the acceptor solution which contains the opposite charged electrode, as depicted in Fig. 1a. The acceptor solution after EME can be subsequently used directly for the analysis by an analytical instrument. In a typical EME, if the analytes are cations, the anode should be placed in the sample and the cathode is in the acceptor solution; while for anions, the opposite direction of current should be applied. With the help of the electric field, the mass transfer in EME is greatly accelerated and the selectivity of the target analytes is further enhanced. Thus, EME has already been used for extraction of various pharmaceuticals from different biological matrices due to sufficient sample clean-up capability and efficient mass transfer [24], [25], [26], [27], [28].
As known, HAL has been extracted from human plasma, urine, serum and whole blood samples by different EME formats such as hollow fiber EME (HF-EME) [29], drop-to-drop EME [30] and micro-EME [31]. For example, HAL was extracted by HF-EME from human plasma and whole blood through an SLM of 1-ethyl-2-nitrobenzene, and the recovery of HAL from diluted human whole blood and plasma were 41% and 42%, respectively [29]. With the µ-EME, HAL was extracted from buffered standard solution, human plasma and serum with recoveries ranged from 25 to 42% [31]. By a drop-to-drop EME, the recovery of HAL from human urine was 40% which was higher than that from the plasma samples [30]. Successful EME of HAL from different biological samples indicated the potential of EME for isolation of antipsychotic drugs from biological specimens, though the reported recovery of HAL was mostly below 50%. In addition, EME from whole blood was more difficult than from water samples or plasma [29], and whole blood and urine are the most common biological specimens in clinic and forensic toxicology laboratories. What's more, as we know, EME of RIS and CPX has never been reported. Therefore, in this study, we aim to improve the EME recovery of HAL and to establish a simple and sensitive EME-LC-MS/MS method using flat membrane-based EME set-up for determination of not only HAL but also RIS and CPX in whole blood and urine samples. Thus, in this work, EME of RIS, HAL and CPX from buffered-water, whole blood and urine samples was investigated, and the developed EME approach was validated using LC-MS/MS. Finally, the applicability of the validated EME-LC-MS/MS method was examined by determining RIS, HAL and CPX in the whole blood and urine from medical treated rats.
Section snippets
Chemicals and materials
Benzyl butyl phthalate (BBP), 2-nitrophenyl octyl ether (NPOE), dibutyl phthalate (DBP), 1-octanol, 1-nonanol, 2-nonanone, trifluoroacetic acid (TFA), haloperidol (HAL) and formic acid (FA) were from Aladdin Chemical Reagent Co. (Shanghai, China). Risperidone (RIS) was purchased from Energy Chemical Co. (Shanghai, China). Chlorprothixene (CPX) was obtained from Tokyo Chemical Industry Co., Ltd. (Shanghai, China). SKF-525A hydrochloride was purchased from Sigma-Aldrich (Shanghai, China).
EME of RIS, HAL and CPX from spiked acidic water samples
According to previous work [24], [25], [27], [28], [29], [30], [31], spiked water samples were frequently used for optimization before EME was applied for biological samples. Thus, EME of RIS, HAL and CPX was first tested using spiked HCl solution (pH 2), and the effect of operation factors such as extraction time, extraction voltage and SLM solvent, on EME efficiency towards RIS, HAL and CPX were systematically studied.
Conclusions
In the present study, CPX, HAL and RIS representing the first and second generation of antipsychotic drugs, respectively were extracted successfully for the first time by EME. The EME recovery of the three antipsychotic drugs from whole blood and urine samples were up to 97%. By combining EME with LC-MS/MS, we have established a sensitive, selective and simple method with capability to determine the antipsychotics of CPX, HAL and RIS in human whole blood and urine samples. The method was
CRediT authorship contribution statement
Xiao Yu: Methodology, Validation, Formal analysis, Investigation, Writing - original draft. Xinlin Li: Methodology, Validation, Formal analysis, Investigation, Writing - original draft. Sunzhao You: Methodology, Validation, Formal analysis, Investigation. Yuhang Shi: Methodology, Validation, Formal analysis, Investigation. Ruiqin Zhu: Methodology, Validation. Ying Dong: Data curation, Writing - original draft, Writing - review & editing. Chuixiu Huang: Conceptualization, Writing - review &
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
This research was funded by National Natural Science Foundation of China (Grant number 21876055 and 81801875), the Fundamental Research Funds for the Central Universities in China (Grant number 2017KFYXJJ021), and the Students Innovation Training Program of Huazhong University of Science and Technology (Grant number 2018FYDC002), and the Hubei Provincial Natural Science Foundation of China (Grant number 2019CFB439).
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These authors contributed equally to this work.