Pharmacokinetics of aconitine as the targeted marker of Fuzi (Aconitum carmichaeli) following single and multiple oral administrations of Fuzi extracts in rat by UPLC/MS/MS
Pharmacokinetics of aconitine as the targeted marker of Fuzi (Aconitum carmichaeli) following single and multiple oral administrations of Fuzi extracts in rat by UPLC/MS/MS
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UPLC/MS/MS 测定大鼠单次和多次口服附子提取物后乌头碱作为附子 (Aconitum carmichaeli) 靶向标志物的药代动力学
DOI：
10.1016/j.jep.2011.08.070
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发表时间：
2012-06-01
影响因子：
5.4
通讯作者：
Liu, Zhongqiu
中科院分区：
文献类型：
--
作者：
Tang, Lan;Gong, Yun;Liu, Zhongqiu
民族药理学相关性：附子，这是经过加工的黄芪的侧根。Debx广泛分布于中国西南各省，因其抗炎和镇痛作用而被公认。乌头碱是附子的主要剧毒成分，是附子的靶向标志物。本研究的目的是研究附子炮制提取物单次和多次给药后乌头碱的体内药代动力学行为，比较单次和多次给药后乌头碱和附子提取物的药代动力学特征，并比较单次和多次给药的差异。方法：采用高效液相色谱（HPLC）法测定附子粗提物中乌头碱的含量，采用快速超高效液相色谱-串联质谱法测定附子粗提物中乌头碱的含量采用超高效液相色谱-串联质谱法（UPLC/MS/MS）研究附子靶向标记物乌头碱的药代动力学行为。大鼠口服乌头碱0.5mg/kg和附子浸膏0.118mg/kg后的绝对生物利用度分别为8.24 ± 2.52%和4.72 ± 2.66%。乌头碱吸收非常快，纯乌头碱的t（max）为30.08 +/- 9.73 min，附子提取物给药的t（max）为58.00 +/- 21.68 min。乌司他丁也以短的半衰期迅速消除（iv.，80.98 +/- 6.40 min）和低蛋白结合率（23.9-31.9%）。单次和多次给药后，乌头碱的所有药代动力学参数均无显著性差异（ANOVA，p > 0.05）。但附子提取物多次给药后乌头碱的吸收比单次给药快得多（t（max）：58.00 +/- 21.68 vs. 20.00 +/- 8.66 min，p < 0.05），血药浓度-时间曲线下面积（AUC）也比单次给药大。本文研究了附子炮制品的药动学行为。乌头碱生物利用度低。单次和多次给药后，未观察到纯乌头碱的药代动力学行为发生变化。相比之下，多次给予加工附子提取物可能会导致其药代动力学行为（AUC和t（max））的变化，这表明多次给药可能会增加乌头碱的生物利用度，这可能会导致其毒性。此外，乌头碱具有低蛋白结合（23.9-31.9%），导致其快速消除。(C)2011爱思唯尔爱尔兰有限公司保留所有权利。
Ethnopharmacological relevance: Fuzi, which is the processed lateral roots of Aconitum Carmichaeli. Debx and is widely distributed over the southwest provinces of China, is recognised for its anti-inflammatory and analgesic effects.Aim of the study: The pharmacokinetic properties of Fuzi are inadequately understood. Aconitine, the primary highly toxic ingredient of Fuzi, is well known as the target marker of Fuzi. The purpose of the present study is to investigate the pharmacokinetic behaviours of aconitine in vivo following single and multiple administrations of processed Fuzi extracts and to compare the pharmacokinetic characteristics of aconitine after administrations of pure aconitine or Fuzi extracts as well as compare the difference at single dose and multiple doses. The in vitro aconitine protein binding in plasma through equilibrium dialysis was also examined.Methods: A high performance liquid chromatography (HPLC) method was developed for the determination of aconitine in Fuzi crude extracts and a fast ultra performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was developed to investigate the pharmacokinetic behaviour of aconitine as the targeted marker of Fuzi.Results: The absolute bioavailability (F%) after the administration of 0.5 mg/kg aconitine and Fuzi extract (0.118 mg/kg aconitine) in rat was 8.24 +/- 2.52% and 4.72 +/- 2.66%, respectively. Aconitine absorption was very fast at the t(max) 30.08 +/- 9.73 min for pure aconitine and 58.00 +/- 21.68 min for Fuzi extract administration. Aconitine was also eliminated rapidly with a short half-life (iv., 80.98 +/- 6.40 min) and a low rate of protein bounding (23.9-31.9%). No significance was observed on all the pharmacokinetics parameters following the single and multiple doses of pure aconitine (ANOVA, p > 0.05). However, the absorption of aconitine after multiple administrations of Fuzi extract was much faster than that of a single dose (t(max): 58.00 +/- 21.68 vs. 20.00 +/- 8.66 min, p < 0.05), and the area under the plasma concentration-time curve (AUC) was higher than that of a single dose.Conclusions: The pharmacokinetic behaviour of processed Fuzi was determined in this paper. The aconitine has low bioavailability. No variation in the pharmacokinetic behaviours of pure aconitine was observed after single and multiple administrations. In contrast, multiple administrations of processed Fuzi extract could result in variations in its pharmacokinetic behaviour in AUC and t(max) indicating that multiple dose might increase the bioavailability of aconitine, which may result in its toxicity. In addition, aconitine has a low protein bounding (23.9-31.9%), resulting in its rapid elimination. (C) 2011 Elsevier Ireland Ltd. All rights reserved.