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Bioavailability and Pharmacokinetics of Anisatin in Mouse Blood by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

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Bioavailability and Pharmacokinetics of Anisatin in Mouse Blood by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Hindawi BioMed Research International Volume 2020, Article ID 8835447, 7 pages https://doi.org/10.1155/2020/8835447 Research Article Bioavailability and Pharmacokinetics of Anisatin in Mouse Blood by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry Xi Bao,1 Xiajuan Jiang,1 Jianshe Ma,2 Xianqin Wang ,2 and Quan Zhou 3 1Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China 2Analytical and Testing Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China 3The Laboratory of Clinical Pharmacy, The People’s Hospital of Lishui, Lishui, China Correspondence should be addressed to Xianqin Wang; [email protected] and Quan Zhou; [email protected] Received 17 September 2020; Revised 25 November 2020; Accepted 15 December 2020; Published 24 December 2020 Academic Editor: Ihsan ul Haq Copyright © 2020 Xi Bao et al. This 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. Background. Anisatin is a neurotoxic sesquiterpene dilactone wildly found in plants of the family Illiciaceae. Due to morphological similarities among Illiciaceae fruits, fatal poisonings are frequent. Objective. This study is aimed at developing a rapid, simple ultra- performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to determine anisatin’s bioavailability in mouse blood and the method’s application to pharmacokinetics. Methods. Blood samples were preprocessed by protein precipitation using acetonitrile. Salicin (internal standard, IS) and anisatin were gradient-eluted by a mobile phase of methanol and water (0.1% formic acid) in a UPLC BEH C18 column. This step involved using an electrospray ionization source of anisatin at a mass-to-charge ratio (m/z) of 327:1 → 127:0 and IS at m/z 285:1 → 122:9 in the negative ion mode with multiple reaction monitoring. Results. The calibration curve ranged from 1 to 2000 ng/ml (r >0:995), with the method’s accuracy ranging from 86.3% to 106.9%. Intraday and interday precision were lower than 14%, and the matrix effect was between 93.9% and 103.3%. The recovery rate was higher than 67.2%. Conclusions. The developed UPLC-MS/MS method was successfully used for a pharmacokinetic study of oral (1 mg/kg) and intravenous (0.5 mg/kg) administration of anisatin to mice—the absolute bioavailability of anisatin in the mouse blood was 22.6%. 1. Introduction the current shikimic acid manufacturing processes, including the tricky extraction of shikimic acid from microorganisms, Humanity has faced many grave respiratory infectious dis- have made significant advances already but not matured ease challenges in this century. Tamiflu (oseltamivir phos- enough to provide for oseltamivir’s production [5, 6]. In case phate), the most clinically effective anti-influenza drug, is of an influenza outbreak, the price increase of Chinese star currently manufactured from shikimic acid, its key precursor anise may give unethical suppliers an incentive to adulterate [1, 2]. Plant products from the Illiciaceae family provide most with cheaper counterfeits and increase prices, whereas lower- shikimic acid, but substantial production is found only in few ing quality; in this scenario, poisonings are inevitable. A mas- species [3–6]. More than 40 species of Illiciaceae are found sive outbreak of such poisonings led the European around the world, many of which are toxic. Directorate for Quality Medicines and the US Food and Drug Chinese star anise (Illicium verum Hook. f., Bajiao) repre- Administration (FDA) to publish guidelines on Chinese star sents a cultivated species with a high content of shikimic acid; anise and its adulteration [9–12]. it is famous for its use as both spice and medicine [3, 6–8]. People sometimes can discriminate and identify Illicium The fruits of the genus Illicium Mangcao (I. henryi. and I. species based on morphology and flavor, but it requires lanceolatum A. C. Smith) are morphologically similar and expertise in Botanics, and in many cases, it does not work easily confounded [7, 8]. According to its growing demand, when the fruits present trace contamination or powder 2 BioMed Research International 2: Daughters of 327ES- O 126.7 100 8.13e5 OH 127.0 O 179.0 327.1 H 126.5 % 178.8 327.4 83.1 179.3 297.0 OH 175.0 HO 101.0 255.2 73.2 199.5 327.6 O OH O 0 m/z 50 100 150 200 250 300 350 400 (a) 100 122.9 4: Daughters of 285ES- 2.98e4 OH 285.0 135.8 O O % 267.1 285.3 HO 217.1 HO OH OH 0 m/z 150 200 250 300 350 400 (b) Figure 1: Chemical structure and mass spectrum of anisatin (a) and salicin (IS; b). mixed. Thus, chemical analytical methods appear to be the used DART-orbitrap-MS; the proposed method is more first choice. According to research [12, 13], anisatin is the straightforward and less labor intensive compared with other specific and principal component causing neurotoxicity, with procedures. It allows for an unambiguous distinction a median lethal dose (LD50) of 1 mg/kg in mice. Extensive between toxic and nontoxic star anise fruits within seconds studies have shown that anisatin’s acute toxic manifestations without any sample pretreatment. include emesis and convulsive seizures. Moreover, studies All the numerous current studies on the Illiciaceae family using a metabolomic approach [14, 15] confirmed that anisa- are about identifying species or poisoning symptoms; none of tin induced convulsive seizures by inhibiting GABAA recep- the research has ever focused on the pharmacokinetics of tors—the neurotoxic mechanisms involved alterations of treatment time window for patients suffering from acute poi- neurotransmission and neuromodulation. soning. Considering the severity of convulsive seizures Several chemical methods focusing on differences among induced by anisatin and the scarcity of reports on its pharma- Illicium species are proposed for anisatin detection [16–19]. cokinetic, it was necessary to establish an analytical method TLC/HSI analyses are suggested to differ among 2 or more to characterize the pharmacokinetics of this dynamic drug species [16, 19]; however, this approach can not reflect the process in mice [23, 24], which were administered with ani- fruits’ overall characteristics and might fail in the face of its satin. To our knowledge, this is the first study on anisatin’s partial adulteration. With the rapid development of the pharmacokinetics in mice, and it may help to understand GC/LC-MS detection technology, the analysis accuracy in better the pharmacokinetics underlying its toxicity. the highly complex chemical field has been dramatically improved. Zhang et al. [20] have developed a sensitive 2. Materials and Methods UPLC-MS/MS method for the quantitative determination of intermediate polarity anisatin in biological samples 2.1. Chemicals. Anisatin (purity >98%) was obtained from (plasma, urine, and vomit). Each analysis’s cycle time was Sigma (St Quentin Fallavier, France), and salicin (IS; purity only 5.0 min, and the limits of quantitation were 2 μg/l for >98%) was obtained from Chengdu Munster Biotechnology plasma samples. According to our knowledge, the best assay Co., Ltd. (Chengdu, China). High-performance liquid chro- has been reported by Schrage and Shen et al. [21, 22], who matography (HPLC) grade formic acid, acetonitrile, and BioMed Research International 3 MRM of 1 channel ES- 2: MRM of 1 channel ES- 327 > 127 (anisatin) 2.65 285.1 > 123 (salicin) 100 100 263 352 2.75 % 2.88 2.98 % 2.84 3.10 2.59 1.53 2.62 1.94 2.23 3.29 0.68 1.67 1.93 2.53 0.12 0.18 0.59 1.17 1.49 0 Time 0 Time 0.50 1.00 1.50 2.00 2.50 3.00 0.50 1.00 1.50 2.00 2.50 3.00 (a) MRM of 1 channel ES- 2: MRM of 1 channel ES- 1.67 100 327 > 127 (anisatin) 100 1.14 285.1 > 123 (salicin) 460 1.99e3 2.71 % % 2.61 2.98 2.65 2.29 2.59 2.70 1.44 1.87 2.61 0 Time 0 Time 0.50 1.00 1.50 2.00 2.50 3.00 0.50 1.00 1.50 2.00 2.50 3.00 (b) MRM of 1 channel ES- 2: MRM of 1 channel ES- 1.67 327 > 127 (anisatin) 1.14 100 100 285.1 > 123 (salicin) 3.49e3 2.35e3 % % 2.65 2.95 2.72 0 Time 0 Time 0.50 1.00 1.50 2.00 2.50 3.00 0.50 1.00 1.50 2.00 2.50 3.00 (c) Figure 2: Representative anisatin (tR =1:67 min) and IS (tR =1:14 min) UPLC/MS/MS chromatograms. (a) A blank blood sample, (b) the blank blood samples spiked with anisatin (0.5 ng/ml) and IS, and (c) blood samples after the oral administration. methanol were obtained from Merck (Darmstadt, Germany), Figure 1 depicts the chemical structure and mass spectrum and ultrapure (type 1) water was obtained through a Milli-Q of anisatin and salicin. water system obtained from Millipore Sigma (Burlington, MA, USA). 2.3. Calibration Standards. We prepared anisatin (1.0 mg/ml) and salicin (1.0 mg/ml) standard solutions in 2.2. Instruments and Conditions. An ACQUITY ultra- methanol and ultrapure water (1 : 1, v/v). Working stan- performance liquid chromatography (UPLC) H-Class system dard solutions of anisatin were conducted by dilution of (Waters Corp, Milford, MA, USA) coupled to a XEVO TQS- stock solutions appropriate with methanol to obtain the micro triple quadrupole mass spectrometer and electrospray desired concentrations of 10, 50, 200, 500, 1000, 2000, ionization (ESI) was employed for the analysis of mouse 5000, 10.000, and 20.000 ng/ml.
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