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Research Article Pharmacokinetic Interaction Study of Ketamine and Rhynchophylline in Rat Plasma by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry

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Research Article Pharmacokinetic Interaction Study of Ketamine and Rhynchophylline in Rat Plasma by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry Hindawi BioMed Research International Volume 2018, Article ID 6562309, 8 pages https://doi.org/10.1155/2018/6562309 Research Article Pharmacokinetic Interaction Study of Ketamine and Rhynchophylline in Rat Plasma by Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry Lianguo Chen,1 Weiwei You,1 Dingwen Chen,1 Yuan Cai,1 Xianqin Wang ,2 Congcong Wen ,3 and Bo Wu 3 1 Te Tird Clinical Institute Afliated to Wenzhou Medical University & Wenzhou People’s Hospital, Wenzhou 325000, China 2Analytical and Testing Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China 3Laboratory Animal Centre, Wenzhou Medical University, Wenzhou, China Correspondence should be addressed to Congcong Wen; [email protected] and Bo Wu; [email protected] Received 7 March 2018; Accepted 11 April 2018; Published 23 May 2018 Academic Editor: Gail B. Mahady Copyright © 2018 Lianguo Chen et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Eighteen Sprague-Dawley rats were randomly divided into three groups: ketamine group, rhynchophylline group, and ketamine combined with rhynchophylline group (n = 6). Te rats of two groups received a single intraperitoneal administration of 30 mg/kg ketamine and 30 mg/kg rhynchophylline, respectively, and the third group received combined intraperitoneal administration of 30 mg/kg ketamine and 30 mg/kg rhynchophylline together. Afer blood sampling at diferent time points and processing, the concentrations of ketamine and rhynchophylline in rat plasma were determined by the established ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. Chromatographic separation was achieved using a UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 �m) with carbamazepine as an internal standard (IS). Te initial mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) with gradient elution. Multiple reaction monitoring (MRM) modes of m/z 238.1 → 179.1 for ketamine, m/z 385.3 → 159.8 for rhynchophylline, and m/z 237.3 → 194.3 for carbamazepine (IS) were utilized to conduct quantitative analysis. Calibration curve of ketamine and rhynchophylline in rat plasma demonstrated good linearity in the range of 1-1000 ng/mL (r > 0.995), and the lower limit of quantifcation (LLOQ) was 1 ng/mL. Moreover, the intra- and interday precision relative standard deviation (RSD) of ketamine and rhynchophylline were less than 11% and 14%, respectively. Tis sensitive, rapid, and selective UPLC-MS/MS method was successfully applied to pharmacokinetic interaction study of ketamine and rhynchophylline afer intraperitoneal administration. Te results showed that there may be a reciprocal inhibition between ketamine and rhynchophylline. 1. Introduction endogenous wind, together with drugs which can warm kidney and activate yang and disperse stagnated liver qi for Ketamine is clinically used for surgical anesthesia [1, 2]. Com- relieving qi stagnation, are used in clinical treatment with monly known as “K powder”, ketamine was epidemically a good therapeutic efect [9, 10]. Terefore, as a common abused in the United States in the early 70s of last century [3, 4]. With the widespread abuse of “party drug” worldwide traditional Chinese medicine in modern detoxifcation com- sincethe1990s,theabuseofketaminequicklyspreadtothe pound, Uncaria is frequently used as the main drug in detox- AsianregionorevenmainlandChina[5,6].Ketaminewas ifcation preparations, such as Kangfuxin capsule, composite ofen abused in entertainment venues, making it one of the Dongyuan Gao, Shutongan capsule, and other preparations. relatively popular new drugs currently [7, 8]. Clinical studies have confrmed that these traditional Chi- Traditional Chinese medicines such as Gastrodia Elata nese medicine compounds are efective in controlling the and Uncaria which can suppress hyperactive liver for calming withdrawal symptoms, relieving mental dependence, and 2 BioMed Research International O N Cl H O O NH N O O H (a) (b) Figure 1: Molecular structure of ketamine (a) and rhynchophylline (b). reducingrelapse[11,12].Moreover,theyaresafeandefective, 2.3. Quality Control Samples Preparation. Te stock solutions with no obvious side efects. of ketamine (1.0 mg/mL), rhynchophylline (1.0 mg/mL), Consequently, in the present study, we established a and carbamazepine (IS) were prepared in methanol-water. UPLC-MS/MS method for the quantifcation of ketamine and Te working standard solution of IS was prepared from rhynchophylline in rat plasma. Meanwhile, we investigated the IS stock solution by dilution with methanol; working the pharmacokinetic interaction of them to explore the anti- solutions for calibration and controls were prepared from ketamine addiction mechanism of rhynchophylline. stock solutions similarly, using methanol diluent. All of the ∘ solutions were stored at 4 Candwerebroughttoroom 2. Materials and Methods temperature before use [14]. 2.1. Chemicals and Reagents. Ketamine (purity > 98%, Fig- 2.4. Calibration Standards Preparation. Ketamine and rhyn- ure 1(a)), rhynchophylline (purity > 98%, Figure 1(b)), and chophylline calibration standards were prepared by spik- carbamazepine (IS, purity > 98%) were purchased from ing blank rat plasma with appropriate amounts of the Chinese Biopharmaceutical Institute (Beijing, China). High working solutions [15]. Calibration plots were ofset to performance liquid chromatography-grade acetonitrile and range between 1 and 1000 ng/mL for ketamine or rhyn- methanol were purchased from Merck Company (Darmstadt, chophylline in rat plasma at 1, 5, 20, 50, 100, 200, 500, Germany).Ultra-purewaterwaspreparedbyaMilli-Qpurif- and 1000 ng/mL. Quality control (QC) samples were pre- cation system (Millipore Bedford, MA). Sprague-Dawley rats paredinthesamemannerasthecalibrationstandards, (200-220 g) were purchased from Laboratory Animal Centre in three diferent plasma concentration levels (2, 90, and of Wenzhou Medical University [2]. 900 ng/mL). 2.2. Instrumentation and Conditions. A UPLC-MS/MS sys- 2.5. Sample Preparation. One hundred microliter of plasma tem with ACQUITY I-Class UPLC and a XEVO TQS-micro sample was mixed with 200 �L of acetonitrile containing 50 triple quadrupole mass spectrometer (Waters Corp., Milford, ng/mL carbamazepine (IS) in a 1.5-mL centrifuge tube and MA,USA)andMasslynx4.1sofware(WatersCorp.)was then extracted by vortexing for 1.0 min to deproteinize the used for data acquisition and instrument control. Chromato- endogenous protein. Afer centrifugation at 14900 g for 10 ∘ graphic separation was achieved using a UPLC BEH C18 min at 4 C, 100 �L of the supernatant was collected into the column (2.1 mm × 50 mm, 1.7 �m) (Waters Corp., Milford, inner lining-pipe of a sample vial. Two microliters of the ∘ MA, USA) maintained at 40 C. Te temperature of UPLC- supernatant was injected into the UPLC-MS/MS system for ∘ MS sampling chamber was maintained at 10 C. Te initial analysis. mobile phase consisted of acetonitrile and water (containing 0.1% formic acid) with gradient elution at a fow rate of 2.6. Pharmacokinetic Study. Eighteen Sprague-Dawley rats 0.4 mL/min. Elution was in a linear gradient, where the (200-220 g) were randomly divided into three groups: acetonitrile content was maintained at 10% between 0 and 0.2 ketamine group, rhynchophylline group, and ketamine com- min, increased to 80% between 0.2 and 1.5 min, maintained at bined with rhynchophylline group (n = 6) [6]. Ketamine 80% between 1.5 and 2.0 min, then decreased to 10% between and rhynchophylline were dissolved in 2% dimethyl sulfox- 2.0 and 2.5 min, and maintained at 10% between 2.5 and 4.0 ide (DMSO). Two groups received a single intraperitoneal min. Te total run time of the analytes was 4 min. (ip) administration (30 mg/kg ketamine and 30 mg/kg Nitrogen was used as the desolvation gas (1000 L/h) and rhynchophylline, respectively), and the third group received cone gas (50 L/h). Ion monitoring conditions were defned combined intraperitoneal (ip) administration of 30 mg/kg ∘ as capillary voltage of 1.5 kV, source temperature of 150 C, ketamine and 30 mg/kg rhynchophylline together. Blood ∘ and desolvation temperature of 500 C [13]. MRM modes samples (0.3 mL) from the tail vein were collected into 1.5 of m/z 238.1 → 179.0 for ketamine, m/z 385.2 → 160.1 for mL heparinized polypropylene tubes at 0.25, 1, 3, 6, 8, 10, and rhynchophylline, and m/z 237.1 → 194.0 for carbamazepine 24 h afer intraperitoneal administration. Te samples were ∘ (IS) were utilized to conduct quantitative analysis, Figure 2. immediately centrifuged at 13000 rpm for 10 min at 4 C. Ten BioMed Research International 3 180329-test-50 29 (1.447) Cm (28:30) 3: Daughters of 238ES+ 100 124.88 3.33e7 178.96 220.04 206.97 (%) 238.11 66.72 162.95 0 50 100 150 200 250 300 (m/z) (a) 180329-test-52 34 (1.717) 4: Daughters of 385ES+ 100 160.13 2.45e6 160.00 159.62 160.25 (%) 269.21 109.77 267.19 70.20 110.09 215.33 353.20 385.15 269.65 0 50 100 150 200 250 300 350 400 (m/z) (b) 180329-test-50 40 (1.986) Cm (39:41) 2: Daughters of 237ES+ 100 194.03 3.59e7 (%) 192.09 237.05 0 50 100 150 200 250 300 (m/z) (c) Figure 2: Mass spectra of ketamine (a), rhynchophylline, (b) and carbamazepine (IS, c). the plasma was transferred to a new 1.5 mL tube and stored at were shown in Figure 3. No interference of visible impurity ∘ −20 Cuntilanalysis. and endogenous substances was observed, indicating that the Plasma concentration versus time data for each rat was analyte of interest and IS were efciently separated by the analyzed by DAS (Drug and Statistics) sofware (version optimized gradient elution procedure. 2.0, China Pharmaceutical University). Te area under the Calibration curve of ketamine and rhynchophylline in plasma concentration-time curve (AUC), mean residence rat plasma demonstrated good linearity in the range of 1- time (MRT), plasma clearance (CL), apparent volume of 1000 ng/mL.
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