title: Pharmacokinetics of mangiferin and its metabolite-Norathyriol, Part 1: Systemic evaluation of hepatic first-pass effect in vitro and in vivo.
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 (Cmax< 3 ng/mL, AUCNTR/AUCMGF< 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 the first systemic study on PK profiles of MGF and NTR in vitro and in vivo, which is important for the interpretation on the poor bioavailability and pharmacodynamics of MGF. © 2016 BioFactors, 42(5):533-544, 2016.
authors.affiliation: Modernization of traditional Chinese medicine, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Tian
authors.affiliation: Modernization of traditional Chinese medicine, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gao
authors.affiliation: College of life and environmental sciences, Shanghai Normal University, Shanghai, People's Republic of China.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of pharmacy ,Harbin University of Commerce, Harbin, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Lian
authors.affiliation: Department of pharmacy ,Harbin University of Commerce, Harbin, People's Republic of China.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Modernization of traditional Chinese medicine, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Xiaozhen
authors.initials: X
authors.lastname: Guo
authors.affiliation: Modernization of traditional Chinese medicine, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
authors.affiliation: Modernization of traditional Chinese medicine, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, People's Republic of China. cghsimm@126.com.
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Modernization of traditional Chinese medicine, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Shanghai, People's Republic of China. zxli0715@126.com.
authors.forename: Chenggang
authors.initials: C
authors.lastname: Huang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004755:Enterobacteriaceae / Q000378:metabolism; D000069196:Gastrointestinal Microbiome; D022781:Hepatocytes / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D061251:Primary Cell Culture; D017208:Rats, Wistar; D014966:Xanthenes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D044004:Xanthones / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D007004:Hypoglycemic Agents; D014966:Xanthenes; D044004:Xanthones; C013592:mangiferin; C069053:norathyriol
keywords: liver; mangiferin; metabolism; norathyriol; pharmacokinetics