Pharmacokinetics and Novel Metabolite Identification of Tartary Buckwheat Extracts in Beagle Dogs Following Co-Administration with Ethanol
Pharmacokinetics and Novel Metabolite Identification of Tartary Buckwheat Extracts in Beagle Dogs Following Co-Administration with Ethanol
复制标题
苦荞提取物与乙醇共同给药后在比格犬体内的药代动力学和新代谢物鉴定
DOI：
10.3390/pharmaceutics11100525
复制
发表时间：
2019-10-01
期刊：
影响因子：
5.4
通讯作者：
Huang, Jiangeng
中科院分区：
文献类型：
--
作者：
Liu, Yuancai;Gan, Jun;Huang, Jiangeng
酒精性肝病（ALD）已成为全球范围内的重要全球公共卫生问题。苦荞提取物具有抗氧化和抗炎活性，对ALD具有潜在的治疗作用。然而，苦荞提取物的体内药代动力学和代谢物鉴定尚未明确阐明。因此，当前手稿旨在研究药物动力学，并确定比格犬经口联合给予苦荞提取物和乙醇后的新型代谢产物。为了支持药代动力学研究，建立了一种简单的LC-MS/MS方法，用于同时测定比格犬血浆中的槲皮素和山奈酚。通过β-葡萄糖醛酸酶和硫酸酯酶水解两种分析物的结合形式，然后使用甲基叔丁基醚进行液-液萃取。此外，还建立了另一种有效的方法，使用先进的超快液相色谱法与Q-Exactive混合四极轨道阱高分辨率质谱仪联用，以鉴定比格犬生物样品（包括尿液、粪便和血浆）中的代谢物。药代动力学研究表明，槲皮素和山奈酚的绝对口服生物利用度分别为4.6%和1.6%。槲皮素和山奈酚的口服生物利用度是有限的，可能是由于吸收不良，显着的首过效应，胆汁消除等，使用高分辨率质谱分析，共9个新的代谢产物被确定为第一次和代谢途径包括甲基化，葡萄糖醛酸化，硫酸化。体内药代动力学和代谢物鉴定结果为苦荞提取物和乙醇在人体中的联合给药提供了临床前支持。
Alcoholic liver disease (ALD) has become a critical global public health issue worldwide. Tartary buckwheat extracts exhibit potential therapeutic effects against ALD due to its antioxidant and anti-inflammatory activities. However, in vivo pharmacokinetics and metabolite identification of tartary buckwheat extracts have not been clearly elucidated. Accordingly, the current manuscript aimed to investigate pharmacokinetics and to identify novel metabolites in beagle dogs following oral co-administration of tartary buckwheat extracts and ethanol. To support pharmacokinetic study, a simple LC-MS/MS method was developed and validated for simultaneous determination of quercetin and kaempferol in beagle dog plasma. The conjugated forms of both analytes were hydrolyzed by β-glucuronidase and sulfatase followed by liquid-liquid extraction using methyl tert-butyl ether. In addition, another effective approach was established using advanced ultrafast liquid chromatography coupled with a Q-Exactive hybrid quadrupole orbitrap high resolution mass spectrometer to identify the metabolites in beagle dog biological samples including urine, feces, and plasma. The pharmacokinetic study demonstrated that the absolute oral bioavailability for quercetin and kaempferol was determined to be 4.6% and 1.6%, respectively. Oral bioavailability of quercetin and kaempferol was limited in dogs probably due to poor absorption, significant first pass effect, and biliary elimination, etc. Using high resolution mass spectrometric analysis, a total of nine novel metabolites were identified for the first time and metabolic pathways included methylation, glucuronidation, and sulfation. In vivo pharmacokinetics and metabolite identification results provided preclinical support of co-administration of tartary buckwheat extracts and ethanol in humans.