细胞色素P450酶介导的异谷黄嘌呤代谢产物在大鼠和人肝微粒体中的药代动力学研究。

PubMed ID
发表日期 2016年Jun月

原始出处 菲特拉皮亚
Fitoterapia
作者 Zhao  Lizhu  Zang  Bin  Qi  Wen  Chen  Fangfang  Wang  Haibo  Kano  Yoshihiro  Yuan  Dan 

文献标题 细胞色素P450酶介导的异谷黄嘌呤代谢产物在大鼠和人肝微粒体中的药代动力学研究。
Pharmacokinetic study of isocorynoxeine metabolites mediated by cytochrome P450 enzymes in rat and human liver microsomes.

文献摘要

异草酚酸(ICN)是钩藤中主要的生物活性四环素类生物碱。广泛用于治疗高血压、血管性痴呆和中风。本研究旨在评估ICN主要代谢产物的血浆药代动力学特征,以及模拟胃肠液(SGF和SIF)、人和大鼠肝微粒体(HLMs和RLMs)以及7种重组人CYP酶在ICN主要代谢途径中的作用。采用uhflc/Q-TOF-MS法测定大鼠口服40mg/kg ICN后血浆中ICN及其7种代谢物的含量。结果表明,18.19-去氢甲氧基苯甲酸(DCA)和5-氧代苯甲酸(5-O-ICA)是ICN的关键和主要代谢产物,而不是ICN本身。进一步研究表明,ICN主要在人或大鼠肝脏中代谢,而cyps2c19、3A4和2D6是导致ICN在人体内转化为DCA和5-O-ICA的主要酶。这些结果对了解四环素类生物碱的药动学性质具有重要意义,并为含钩藤的中药制剂与主要由CYP3A4和CYP2C19代谢的降压药合用提供了有益的信息。


Isocorynoxeine (ICN) is one of the major bioactive tetracyclic oxindole alkaloids found in Uncaria rhynchophylla (Miq.) Jacks. that is widely used for the treatment of hypertension, vascular dementia, and stroke. The present study was undertaken to assess the plasma pharmacokinetic characteristics of major ICN metabolites, and the role of simulated gastric and intestinal fluid (SGF and SIF), human and rat liver microsomes (HLMs and RLMs), and seven recombinant human CYP enzymes in the major metabolic pathway of ICN. A rapid, sensitive and accurate UHPLC/Q-TOF MS method was validated for the simultaneous determination of ICN and its seven metabolites in rat plasma after oral administration of ICN at 40mg/kg. It was found that 18.19-dehydrocorynoxinic acid (DCA) and 5-oxoisocorynoxeinic acid (5-O-ICA) were both key and predominant metabolites, rather than ICN itself, due to the rapid and extensive metabolism of ICN in vivo. The further study indicated that ICN was mainly metabolized in human or rat liver, and CYPs 2C19, 3A4 and 2D6 were the major enzymes responsible for the biotransformation of ICN to DCA and 5-O-ICA in human. These findings are of significance in understanding of the pharmacokinetic nature of tetracyclic oxindole alkaloids, and provide helpful information for the clinical co-administration of the herbal preparations containing U. rhynchophylla with antihypertensive drugs that are mainly metabolized by CYP3A4 and CYP2C19.


获取全文 10.1016/j.fitote.2016.04.008