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Focus on China TOP ARTICLES SUPPLEMENT Powered by Focus on China TOP ARTICLES SUPPLEMENT CONTENTS RESEARCH ARTICLE: Simultaneous determination of hyzetimibe and its main active metabolite in plasma by LC–MS/MS and its application in PK study Bioanalysis Vol. 7 Issue 15 RESEARCH ARTICLE: Highly specific and sensitive immunoassay for the measurement of prostaglandin E2 in biological fluids Bioanalysis Vol. 7 Issue 19 REVIEW: Derivatization methods for LC–MS analysis of endogenous compounds Bioanalysis Vol. 7 Issue 19 METHODOLOGY: Development of an Excel-based laboratory information management system for improving workflow efficiencies in early ADME screening Bioanalysis Vol. 8 Issue 2 Research Article For reprint orders, please contact [email protected] 7 Research Article 2015/07/30 Simultaneous determination of hyzetimibe and its main active metabolite in plasma by LC–MS/MS and its application in PK study Bioanalysis Background: Hyzetimibe is a new compound belonging to a novel class of selective Jinliang Chen1, Honggang cholesterol absorption inhibitors. A simple, highly sensitive LC–MS/MS method has Lou1, Bo Jiang1, Rong Shao1, been developed for the quantification of hyzetimibe and its main active metabolite, Zourong Ruan1 ,1 hyzetimibe-glucuronide, in human plasma. Results: Analytical samples were prepared & Jian’an Wang* 1Center of Clinical Pharmacology, using a protein precipitation method coupled with a concentration process. The the Second Affiliated Hospital of linearity of this method was established for concentrations in the ranges of 0.05–50 Zhejiang University School of Medicine, and 0.5–500 ng/ml for hyzetimibe and hyzetimibe-glucuronide, respectively. The Hangzhou, Zhejiang, China accuracy and precision of the method varied from 97.9 to 105% and 2.6 to 7.4%, *Author for correspondence: respectively. Conclusion: This study represents the first reported example of an Tel.: +86 0571 8778 3759 Fax: +86 0571 8778 3969 LC–MS/MS assay for the simultaneous quantification of hyzetimibe and its main active [email protected] metabolite, hyzetimibe-glucuronide, in human plasma. Furthermore, this method has been successfully applied to a PK study. Hyzetimibe (1-[4-fluorophenyl]-3[R]-[3-(4- pletely converted to its active metabolite fluorophenyl)-4-hydroxybut-2(Z)-enyl]-4 hyzetimibe-glucuronide (1-O-[4-(trans- [S]-[4-hydroxyphenyl]-2-azetidinone) is a [2S,3R]-1-[4-Fluorophenyl]-3[R]-[3-(4- new cholesterol absorption inhibitor fluorophenyl)-4-hydroxybut-2(Z)-enyl]-4 that blocks the intestinal absorption of cho- [S]-[4-hydroxyphenyl]-2-azetidinyl) lesterol and phytosterols. As novel choles- phenyl]-β-d-glucuronic acid). On aver- terol-lowering agents, cholesterol absorption age, the AUC of hyzetimibe-glucuronide inhibitors can be used to significantly lower was approximately 90% of the exposure of the levels of low-density lipoprotein choles- the total amount of the compounds in the terol (LDL-C) in humans, when they are plasma (i.e., hyzetimibe plus hyzetimibe- used alone or in combination with statins [1] . glucuronide) [2]. In a similar manner to 15 The results of an initial PD study in healthy ezetimibe, significant levels of enterohepatic subjects showed that the once-daily adminis- recycling occurred following the oral admin- tration of hyzetimibe led to significant reduc- istration of hyzetimibe, which resulted in tions in LDL-C by 7.8–19.7% [2]. The results multiple peaks in the concentration–time 2015 of a similar study using the first reported profiles for this drug [4]. For this reason, cholesterol adsorption inhibitor, ezetimibe, there is an urgent need for the development revealed an 18.5% reduction in LDL-C in of a reliable-validated method for the PK subjects [3]. Hyzetimibe appears to be safe study of hyzetimibe in humans, especially and well tolerated, and the results of all of for the concentration of hyzetimibe-gluc- the preclinical studies and Phase I clinical uronide. We previously reported the first- trials to have been conducted to date suggest in-human study of hyzetimibe, where pro- that this drug could be used as a potential tein precipitation was used to allow for the treatment for hypercholesterolemia. simultaneous determination of hyzetimibe Hyzetimibe is rapidly absorbed in and hyzetimibe-glucuronide [2]. To the best the small intestine following its oral of our knowledge, there have been no other administration and is almost com- reports in the literature pertaining to the part of 10.4155/BIO.15.114 © 2015 Future Science Ltd Bioanalysis (2015) 7(15), 1857–1867 ISSN 1757-6180 1857 Research Article Chen, Lou, Jiang, Shao, Ruan & Wang Key terms has also been used to support a PK study in healthy subjects. Cholesterol absorption inhibitor: Agents that act at the brush border of the small intestine to inhibit the intestinal absorption of dietary and biliary cholesterol across the Materials & methods intestinal wall, leading to a decrease in the delivery of Chemicals & materials intestinal cholesterol to the liver. Hyzetimibe (Lot no.: 120101, 99.0%) and hyzeti- Isotope-labeled IS: Nonradioactive compounds where mibe-glucuronide (Lot no.: 20110413, 91.18%) were one or more of the atoms have been exchanged with an provided by Zhejiang Hisun Pharmaceutical Co., isotope to give an IS that can be readily identified by mass Ltd (Zhejiang, China). The isotope-labeled IS spectral analysis for determination. (hyzetimibe-d4 and hyzetimibe-glucuronide-d4) were obtained from Shanghai ChemPartner Co., systematic determination of hyzetimibe and hyzeti- Ltd (Shanghai, China). The structures of these com- mibe-glucuronide in plasma. The chemical structures pounds are shown in Figure 1. Acetonitrile and metha- of hyzetimibe and ezetimibe are very similar, and the nol were purchased as the HPLC grade from Merck methods reported in the literature for the determi- (Darmstadt, Germany). HPLC-grade water was puri- nation of ezetimibe involve the individual quanti- fied using a Milli-Q water purification system (Milli- fication of free ezetimibe and total ezetimibe (after pore Corp., MA, USA). All of the other chemicals used hydrolysis) [5,6,7]. However, these methods could be in the current study were purchased as the analytical complicated by the hydrolysis of ezetimibe, because grade from Sinopharm Chemical Reagent Company this process could affect the final concentration. (Shanghai, China). In this study, we have developed a simple and highly sensitive LC–MS/MS method with a LLOQ, LC–MS/MS which has been combined with protein precipitation The LC system consisted of a Nexera LC (LC-30AD), and concentration processes to allow for the simulta- a Nexera column oven (CTO-30A), which was set neous quantification of the plasma concentrations of at 40°C (Shimadzu, Kyoto, Japan), and an autos- hyzetimibe and hyzetimibe-glucuronide. This method ampler (PAL HTC-xt), which was set at 4°C (CTC, Zwingen, Switzerland). The analytes were separated over a 1.8 μm Agilent ZORBAX SB-C18 column (50 × 2.1 mm; CA, USA) under gradient conditions using water (mobile phase A) and methanol (mobile phase B) as the eluents. The gradient cycle consisted of an initial 1.8 min isocratic elution with 5% mobile phase B, followed by a linear increase in mobile phase B to 95% over a period of 2 min. The column was then eluted for 0.7 min with 95% mobile phase B before being eluted with 5% mobile phase B for 1 min. The total run time for each injection was therefore 5.5 min at a flow rate of 0.3 ml/min with a backpressure of approximately 30 MPa. The LC system was coupled to a QTRAP® 5500 System (AB SCIEX, CA, USA) fitted with a Turbo V™ ionization source interface, which was operated in the negative ion mode. Quantification was performed using the multiple reaction monitoring mode to monitor the following transitions: m/z 420.0→283.0 (hyzetimibe), m/z 595.8→283.0 (hyzetimibe-gluc- uronide), m/z 424.0→287.0 (hyzetimibe-d4) and m/z 599.9→287.0 (hyzetimibe-glucuronide-d4). The ARE YOU IN THE ZONE? source dependent parameters, which were maintained for all analytes were as follows: curtain gas (CUR), nitrogen; flow rate, 30 l/min; collision gas (CAD), Connect and interact with medium; ionspray voltage (IS), –4500 eV; tempera- ture (TEM), 500°C; ion source gas 1 (GS 1) flow rate, international bioanalysts 40 l/min; ion source gas 2 (GS 2) flow rate, 60 l/min. 1858Join today Bioanalysis (2015) 7(15) future science group www.Bioanalysis-Zone.com Simultaneous determination of hyzetimibe & its metabolite in plasma Research Article A B 283.0 283.0 OH 7. 5e6 O GlGlu 2.6e8 OH 7. 0e6 OH 2.4e8 6.5e6 N 2.2e8 N F O 6.0e6 F O 2.0e8 F 5.5e6 F 1.8e8 5.0e6 1.6e8 4.5e6 1.4e8 4.0e6 1.2e8 3.5e6 112.8 3.0e6 1.0e8 2.5e6 8.0e7 2.0e6 6.0e7 1. 5e6 174.6 - 4.0e7 [M-H] 265.2 265.2 420.0 1. 0e6 [M-H]- 595.8 2.0e7 5.0e5 117. 1 390.0 128.9156.8 214.1 459.0 0.0 0.0 100 140180 220 260 300 340 380 420 100150 200 250 300 350 400 450 500 550 600 m/z (Da) m/z (Da) C D 287. 0 287. 0 D OH D 1. 20e8 3.6e7 O Glu OH D D OH D 1. 10e8 D N D 3.2e7 N 1. 00e8 F O D 2.8e7 F O 9.00e7 F F 8.00e7 2.4e7 7. 00e7 2.0e7 6.00e7 1. 6e7 112.9 5.00e7 174.9 4.00e7 1. 2e7 269.0 3.00e7 - [M-H] 8.0e6 424.0 2.00e7 [M-H]- 4.0e6 599.9 1. 00e7 268.9 128.7156.9 394.1 218.0 255.1 463.1 0.0 0.0 100 140180 220 260 300 340 380 420 100150 200 250 300 350 400 450 500 550 600 m/z (Da) m/z (Da) Figure 1.
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