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Dynamic Variation Patterns of Aconitum Alkaloids in Daughter Root of Aconitum Carmichaelii (Fuzi) in the Decoction Process Based

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Dynamic Variation Patterns of Aconitum Alkaloids in Daughter Root of Aconitum Carmichaelii (Fuzi) in the Decoction Process Based Iranian Journal of Pharmaceutical Research (2016), 15 (1): 263-273 Copyright © 2016 by School of Pharmacy Received: January 2014 Shaheed Beheshti University of Medical Sciences and Health Services Accepted: April 2014 Original Article Dynamic Variation Patterns of Aconitum Alkaloids in Daughter Root of Aconitum Carmichaelii (Fuzi) in the Decoction Process Based on the Content Changes of Nine Aconitum Alkaloids by HPLC- MS- MS Heng Luoa, Zhifang Huangb, Xiaolong Tangc, Jinhai Yib*, Shuiying Chend, Andong Yanga and Jun Yanga aCentre of Instrumental Analysis, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, P. R. China. bInstitute of Traditional Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610041, P. R. China. cCollege of Pharmaceuitcal Science,Chengdu University of Traditional Chinese Medicine, Chengdu, 611731, P. R. China. dFunan Jinsha Community Health Service Center of Qingyang District, Chengdu, 610072, P. R. China. Abstract The chemical components in the decoctions of Chinese herbal medicines are not always the same as those in the crude herbs because of the insolubility or instability of some compounds. In this work, a high-performance liquid chromatography (HPLC) coupled with electrospray ionization (ESI) tandem mass spectrometry method was developed to explore dynamic variation patterns of aconitum alkaloids in Fuzi during the process of decocting aconite root. The fragmentation patterns of aconitum alkaloids using ESI and collision-induced dissociation (CID) techniques were reported. This assay method was validated with respect to linearity (r2 > 0.9950), precision, repeatability, and accuracy (recovery rate between 94.6 and 107.9%).The result showed that the amounts of aconitum alkaloids in the decoction at different boiling time varied significantly. In the decoction process, the diester- type alkaloids in crude aconite roots have transformed into Benzoylaconines or aconines. Keywords: Fuzi; Aconite decoction; Aconitum alkaloids; Dynamic variation; HPLC- MS- MS. Introduction positive inotropic effects; and regulation of neurological disorders. However, the high Fuzi, the daughter root of Aconitum toxicity risks and narrow therapeutic ranges carmichaelii Debx. (Ranunculaceae), is official limit the medicinal application on a larger scope. in Chinese Pharmacopeia (2010 version) (1). Typical symptoms of intoxication include rapid- It has been clinically used for the treatment onset facial and extremity paresthesias, chest of rheumatism, neuralgia, and cardiac discomfort, hypotension, and arrhythmias (4, 5). complaints for thousand years (2, 3). The The main active components of Fuzi are following pharmacological effects of Aconitum aconitum alkaloids. Aconitum alkaloids consist alkaloid have been described: analgesic, anti- of aconitines (diester-diterpenoid alkaloids), inflammatory, and anti-rheumatic activity; benzoylaconines (monoester-diterpenoid alkaloid) and aconines (amine alcohol-type alkaloids) as * Corresponding author: shown in Figure 1 (6). The high toxicity levels of E-mail: [email protected] aconitum alkaloids are considered to be derived Luo H et al. / IJPR (2016), 15 (1): 263-273 from its aconitines. It is well-known that the above were related to raw aconite roots or processing of raw herbal materials is one of biological samples without clear indications the characteristics of the Chinese medicine. of Fuzi decoctions. It should be accepted that Removing or reducing toxicity is the main decocting is an easy way to reduce toxicity of objective for the processing of Fuzi. During Fuzi. processing, aconitines molecules lose their In the present study, we aimed to develop acetyl group at C8 and become benzoylaconines. and validate a sensitive and accurate HPLC-MS- The toxicity of the latter is 1/100–400 of the MS method for simultaneous determination of former. Benzoylaconines can further lose 9 aconitum alkaloids in the decoctions of Fuzi, the benzoyl ester group at C14 to convert into including aconitine (AC), mesaconitine (MA), aconines, whose toxicity is further reduced (6- hypaconitine (HA), benzoylaconine (BAC), 8). Fortunately, this chemical reaction has been benzoylmesaconine (BMA), benzoylhypaconine unconsciously applied for thousands of years in (BHA), aconine, mesaconine and hypaconine. the Chinese medicine to reduce toxicity in the During the method development, multiple processing of aconite herbs. The processing of reaction monitoring (MRM) mode was Fuzi is done by soaking, heating and decocting employed and an electrospray ionization source it in alkaline or water solution (4, 8-12). This was operated in positive mode. To the best of process has no significant impacts on bioactivity our knowledge, this is the most comprehensive and pharmacological effects (1, 13 and 14). report on the quantitative analysis of Fuzi In fact, the toxicity of these herbs can be decoctions. This paper explores dynamic indicated by the amount of aconitum alkaloids. variation patterns of aconitum alkaloids during Therefore, the development of a rapid, valid, and the process of decocting aconite root so as to sensitive method to simultaneously, qualitatively, provide a reference for its further development and quantitatively assessing the aconitum and utilization. alkaloids in Fuzi decoction is necessary and significant to ensure its safety and effectiveness Experimental in the areas of clinical drug use. Many methods for the determination of Chemical reagents and materials aconitum alkaloids have been reported, such AC, MA, HA, BAC, BMA, BHA, and as high-performance liquid chromatography Lannaconitine (IS) were purchased from National (HPLC) (15, 16), thin-layer chromatography Institute for Food and Drug Control (Beijing, (TLC) (17, 18), capillary electrophoresis (19). China). Aconine, Mesaconine, Hypaconine Nevertheless, these methods often required were extracted from Fuzi and purified in our complete resolution of all constituents, which laboratory. These compounds were identified were time-consuming, and the sensitivities of using ESI-MS, 1H and 13C NMR techniques, and these methods were very low. There have also by comparing their experimental and reported been other methods, such as gas chromatography- spectroscopic data. The purity of all constituents tandem mass spectrometry (GC-MS) (20-23), is above 98% by HPLC analysis. liquid chromatography-fast atom bombardment Six batches of Fuzi were purchased from (LC-FAB-MS) (24). However, the GC-MS (20- Lotus Pond Chinese Medicinal Herbs Wholesale 23) method used trimethyl-silyl derivatization Market of Chengdu in Sichuan province, and the extraction procedure was tedious. The China, in November 2012, and authenticated LC-FAB-MS (24) methods achieved a high by Prof. Guang-Ming Shu (the Department of sensitivity, but the elution time was still very long. Pharmacognosy, Sichuan Academy of Chinese Liquid chromatography–mass spectrometry Medicine Sciences (Chengdu, China)). HPLC- (LC-MS) (25, 26) and LC coupled with tandem grade formic acid was purchased from Tianjin mass spectrometry (LC-MS-MS) (27, 28) have Kermel Chemical Reagents Development Center been proposed for the determination of aconitum (Tianjin, China). HPLC-grade methanol was alkaloids in biological samples. However, all purchased from Fisher Scientific (Fair lawn, New pharmacological and clinical studies mentioned Jersey, USA). Ultrapure water was prepared on 264 Dynamic Variation Patterns of Aconitum Alkaloids OH OCH3 R 1 R H 5 R2 N OH R4 R3 OCH3 H3CO + Name [M+H] R1 R2 R3 R4 R5 Aconitine 646.5 OCH3 C2H5 OH OAc OBz Mesaconitine 632.5 OCH3 CH3 OH OAc OBz Hypaconitine 616.5 OCH3 CH3 H OAc OBz Benzoylaconine 604.4 OCH3 C2H5 OH OH OBz Benzoylmesaconine 590.3 OCH3 CH3 OH OH OBz Benzoylhypaconine 574.3 OCH3 CH3 H OH OBz Aconine 500.3 OCH3 C2H5 OH OH OH Mesaconine 486.4 OCH3 CH3 OH OH OH Hypaconine 470.3 OCH3 CH3 H OH OH Figure 1. Chemical structures of 9 compounds. a TCEH-RO/40 Reagent Water System (Beijing mode with the spray voltage set at 4,000 Aisitaike Technology Development Co., Ltd, V. Nitrogen was used as nebulizer gas and Beijing, China) for the preparation of samples nebulizer pressure was set at 40 psi with a and buffer solutions. All other reagents were of source temperature of 105 ˚C. Desolvation gas analytical grade. (nitrogen) was heated to 350 ˚C and delivered at a flow rate of 10 L min-1. For collision- induced Instrumentation and conditions dissociation (CID), high purity nitrogen was Chromatographic analysis was performed on used as collision gas at a pressure of about 0.15 an Agilent Rapid Resolution HPLC system, 1200 MPa. Multiple reaction monitoring (MRM) series (Agilent Corporation, MA, and USA) mode was used for the quantification at m/z equipped with a binary pump, micro degasser, 646.5→586.4 for AC, m/z 632.5→572.5 for an auto plate-sampler, and thermostatic column MA, m/z 616.5→556.5 for HA, m/z 604.4 compartment. Separation was performed on a →554.4 for BAC, m/z 590.3→540.3 for BMA, Shiseido Capcell Pak C18 (3 × 100 mm, 3 μm) m/z 574.3→542.3 for BHA, m/z 500.3→450.4 column. The mobile phase was composed of for Aconine, m/z 486.4→436.2 for Mesaconine, 0.1% formic acid (A) and acetonitrile (B), with m/z 470.3→438.2 for Hypaconine, m/z a gradient elution as follows: 0 min: 12% (B), 3 585.4→356.3 for Lannaconitine (IS), Table 1 min: 40% (B), 10min: 70% (B), 12 min: 80% (B), shows the optimized MRM parameters for 12.01 min: 12% (B). The column temperature detected drugs and IS. The peak widths of was set at 30 ˚C. The flow rate was 0.4 mL min-1. precursor and product ions were maintained Mass spectrometry was performed using at 0.7 amu at half-height in the MRM mode. an Agilent 6410 triple quadrupole mass Data acquisition was performed with Mass spectrometer equipped with an electrospray Hunter Workstation (Agilent Technologies, ionization source (ESI) in the positive USA). 265 Luo H et al. / IJPR (2016), 15 (1): 263-273 Preparation of standard solutions by spiking the lowest point of calibrator with Each accurately weighted standard was precision and accuracy ≤ 20% which resulted in dissolved in methanol to give stock solutions.
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