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Rapid identification and pharmacokinetic studies of multiple active alkaloids in rat plasma through UPLC-Q-TOF-MS and UPLC-MS/MS after the oral administration of Zanthoxylum nitidum extract.
Journal of Pharmaceutical and Biomedical Analysis ( IF 3.1 ) Pub Date : 2020-03-20 , DOI: 10.1016/j.jpba.2020.113232
Qiyan Lin 1 , Hongli Pu 1 , Huida Guan 1 , Chao Ma 1 , Yunpeng Zhang 1 , Wenzheng Ding 1 , Xuemei Cheng 1 , Lili Ji 1 , Zhengtao Wang 1 , Changhong Wang 1
Affiliation  

Zanthoxylum nitidum (Roxb.) DC. (ZN) belongs to the genus Zanthoxylum of Rutaceae and has various chemical ingredients and pharmacologic effects. Alkaloids are its main active constituents responsible for diverse pharmacologic effects, such as anti-tumor, anti-bacterial, anti-inflammatory, and analgesic activities. The chemical and pharmacological effects of ZN are well reported, but the in vivo pharmacokinetic profiles of its main active alkaloids are poorly investigated. This study aims to elucidate the absorbed constituents and pharmacokinetic behavior of main active ingredients in rat plasma after the oral administration of ZN extract. The absorbed constituents in rat plasma were qualitatively analyzed using ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination and pharmacokinetic studies of dihydrochelerythrine (DHCHE), nitidine chloride (NIT), chelerythrine (CHE), sanguinarine (SAN), liriodenine (LIR), skimmianine (SKI), γ-fagarine (FAG), and dictamnine (DIC) in rat plasma. Eighteen prototypes and metabolites were identified according to exact mass, characteristic diagnostic fragment ions, and reference standards. The established UPLC-MS/MS quantitative method met the requirements of FDA for biological analysis methods. Method validation showed that this method has good linearity (r ≥ 0.9910), precision (RSD ≤ 18.63 %), accuracy (88.11 %-117.50 %), and stability. The limit of detection (LOD) could reach 1 ng/mL, and the limit of quantitation could reach 2 ng/mL. The plasma drug concentration of benzophenanthridine alkaloids, such as NIT, CHE, and DHCHE, were still low even after dose differences were deducted. For the furan quinoline alkaloids (such as SKI, FAG, and DIC), only SKI showed high plasma drug concentration, although SKI content comprised only approximately 1/6 of benzophenanthridine alkaloids. This study is the first to simultaneously determine the above-mentioned active alkaloids in rat plasma and would contribute to the comprehensive understanding of in vivo pharmacokinetic behavior on active alkaloids in ZN extract.

中文翻译:

口服花椒提取物后,通过UPLC-Q-TOF-MS和UPLC-MS / MS对大鼠血浆中多种活性生物碱进行快速鉴定和药代动力学研究。

花椒硝酸盐(Roxb。)DC。(ZN)属于芸苔科的花椒属(Zanthoxylum),具有多种化学成分和药理作用。生物碱是其主要活性成分,负责多种药理作用,例如抗肿瘤,抗细菌,抗炎和镇痛活性。ZN的化学和药理作用已得到很好的报道,但其主要活性生物碱的体内药代动力学特征研究却很少。本研究旨在阐明口服ZN提取物后大鼠血浆中主要活性成分的吸收成分和药代动力学行为。使用超高效液相色谱和四极杆飞行时间质谱(UPLC-Q-TOF-MS)对大鼠血浆中吸收的成分进行定性分析。开发了具有三重四极杆质谱(UPLC-MS / MS)方法的超高效液相色谱仪,用于同时测定二氢白屈菜红碱(DHCHE),氯化亚硝胺(NIT),白屈菜红碱(CHE),血红碱(SAN)和药代动力学研究,血浆中的鹅绒素(LIR),skimmianine(SKI),γ-fagarine(FAG)和dictamnine(DIC)。根据精确质量,特征性诊断碎片离子和参考标准,鉴定出18种原型和代谢物。建立的UPLC-MS / MS定量方法符合FDA对生物分析方法的要求。方法验证表明,该方法具有良好的线性(r≥0.9910),精度(RSD≤18.63%),准确性(88.11%-117.50%)和稳定性。检测限(LOD)可能达到1 ng / mL,定量限可以达到2 ng / mL。即使扣除了剂量差异,二苯并菲啶生物碱(如NIT,CHE和DHCHE)的血浆药物浓度仍然很低。对于呋喃喹啉生物碱(例如SKI,FAG和DIC),尽管SKI含量仅占苯并菲啶生物碱的约1/6,但只有SKI显示出较高的血浆药物浓度。这项研究是第一个同时测定大鼠血浆中上述活性生物碱的方法,将有助于全面了解ZN提取物中活性生物碱的体内药代动力学行为。尽管SKI含量仅占苯并菲啶生物碱的约1/6,但只有SKI表现出较高的血浆药物浓度。这项研究是第一个同时测定大鼠血浆中上述活性生物碱的方法,将有助于全面了解ZN提取物中活性生物碱的体内药代动力学行为。尽管SKI含量仅占苯并菲啶生物碱的约1/6,但只有SKI表现出较高的血浆药物浓度。这项研究是第一个同时测定大鼠血浆中上述活性生物碱的方法,将有助于全面了解ZN提取物中活性生物碱的体内药代动力学行为。
更新日期:2020-03-20
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