Hydrastine Pharmacokinetics and Metabolism after a Single Oral Dose of Goldenseal (Hydrastis canadensis) to Humans
Hydrastine Pharmacokinetics and Metabolism after a Single Oral Dose of Goldenseal (Hydrastis canadensis) to Humans
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DOI：
10.1124/dmd.114.059410
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发表时间：
2015-04-01
影响因子：
3.9
通讯作者：
Hendrickson, Howard P.
中科院分区：
文献类型：
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作者：
Gupta, Prem K.;Barone, Gary;Hendrickson, Howard P.
11名健康受试者口服2.7g含78 mg海斯汀的黄花丹补充剂后，研究了海斯丁的吸收和代谢。连续48小时采血，24小时采尿。液质联用(LC-MS/MS)测定血药浓度和尿药浓度。用非房室法计算海斯汀的药代动力学参数。最大血药浓度(C-max)为225+/-100 ng/ml，T-max为1.5+/-0.3小时，曲线下面积为6.4+/-4.1 ng/mlxkg。消除半衰期为4.8+/-1.4小时。采用高效液相色谱-高分辨质谱联用技术对血清和尿液中的海斯汀代谢物进行鉴定。采用精确质量测量、中性损失扫描、四极杆飞行时间法(Q-ToF)和三重四极杆仪积离子扫描等多种质谱学技术对海斯汀代谢物进行鉴定。用牛β-葡萄糖醛酸苷酶和螺旋果皮糖苷酶/葡萄糖醛酸苷酶制剂对葡萄糖醛酸苷和硫酸盐结合物进行水解，进一步证实了II相代谢产物的同一性。海斯汀被发现经历了快速和广泛的I期和II期代谢。在海斯汀的第一阶段生物转化过程中，观察到内酯水解形成的醇基还原、O-脱甲基、N-脱甲基、羟化、芳构化、内酯水解和脱氢为酮基。第二相代谢产物主要是葡萄糖醛酸苷和硫酸盐结合物。海斯汀经历了广泛的生物转化，一些代谢物可能具有药理活性。这方面还需要进一步研究。
The disposition and metabolism of hydrastine was investigated in 11 healthy subjects following an oral dose of 2.7 g of goldenseal supplement containing 78 mg of hydrastine. Serial blood samples were collected for 48 hours, and urine was collected for 24 hours. Hydrastine serum and urine concentrations were determined by Liquid Chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters for hydrastine were calculated using noncompartmental methods. The maximal serum concentration (C-max) was 225 +/- 100 ng/ml, T-max was 1.5 +/- 0.3 hours, and area under the curve was 6.4 +/- 4.1 ngxh/mlxkg. The elimination half-life was 4.8 +/- 1.4 hours. Metabolites of hydrastine were identified in serum and urine by using liquid chromatography coupled to high-resolution mass spectrometry. Hydrastine metabolites were identified by various mass spectrometric techniques, such as accurate mass measurement, neutral loss scanning, and product ion scanning using Quadrupole-Time of Flight (Q-ToF) and triple quadrupole instruments. The identity of phase II metabolites was further confirmed by hydrolysis of glucuronide and sulfate conjugates using bovine beta-glucuronidase and a Helix pomatia sulfatase/glucuronidase enzyme preparation. Hydrastine was found to undergo rapid and extensive phase I and phase II metabolism. Reduction, O-demethylation, N-demethylation, hydroxylation, aromatization, lactone hydrolysis, and dehydrogenation of the alcohol group formed by lactone hydrolysis to the ketone group were observed during phase I biotransformation of hydrastine. Phase II metabolites were primarily glucuronide and sulfate conjugates. Hydrastine undergoes extensive biotransformation, and some metabolites may have pharmacological activity. Further study is needed in this area.