Pharmacokinetics of mangiferin and its metabolite—Norathyriol, Part 1: Systemic evaluation of hepatic first‐pass effect in vitro and in vivo

作者：Xiaoting Tian, Yu Gao, Xu Zhou, Shan Lian, Yuanjie Ma, Xiaozhen Guo, Pei Hu, Zhixiong Li, Chenggang Huang · 发表于：BioFactors · 年份：2016 · DOI：10.1002/biof.1291 · 被引用次数：33 · 研究领域：Mangiferin and Mango Extracts、Ginger and Zingiberaceae research、Natural Antidiabetic Agents Studies

Abstract Mangiferin (MGF), a glucoside of xanthone existing in phytomedicines and food, is increasingly attracting attention on diabetes treatment, while the underlying mechanism leading to its low oral bioavailability is unclear. Norathyriol (NTR), an active metabolite with hypoglycemic activity and its exposure after MGF dosing remains unclear. Hence, a rapid and sensitive LC‐MS/MS method was established and validated to determine MGF and NTR and applied in the PK study in rats. Correspondingly, the in vitro experiments on temperature‐dependent uptake, and MGF metabolism in hepatocyte and enterobacteria samples were performed. Results revealed that hepatic first‐pass effect slightly contributed to the poor bioavailability of MGF, based on the MGF exposure in portal vein plasma was nearly similar to that in systemic plasma, and the MGF accumulation in the liver was limited, so was that of NTR. Correspondingly, the in vitro study revealed the MGF uptake was mainly dependent on poor passive transport, possibly leading to its limited hepatic metabolism and accumulation. Moreover, the NTR exposure remained considerably low ( C max < 3 ng/mL, AUC NTR /AUC MGF < 3%) in plasma after single MGF dosing, corresponding to its tiny proportion (0.1%) of MGF in MGF‐incubated enterobacteria samples. However, given the low generation and elimination rates of NTR, NTR might accumulate in plasma and exert effects after repeated MGF dosing, although requires further study. This work is t...