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 firstpass 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 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.

Mangiferin Improves Hepatic Lipid Metabolism Mainly Through Its Metabolite-Norathyriol by Modulating SIRT-1/AMPK/SREBP-1c Signaling

“…From a drug metabolism perspective, as a xanthone carbon glycoside, low solubility of MGF in most aqueous and organic solvents causes difficulties for it passing through intestinal blockage and keep maintaining its original structure after liver metabolism. Previous studies by another group showed that the bioavailability of oral MGF was 1.2% in rats ( Tian et al, 2016 ), implying that MGF might not be the final active compound regulating lipid metabolism. Using phytochemical methods, we isolated the metabolites of MGF from rat urine after long term oral administration.…”

Identifying the active components of Baihe–Zhimu decoction that ameliorate depressive disease by an effective integrated strategy: a systemic pharmacokinetics study combined with classical depression model tests

“…Although they exhibit various bioactivities in vivo, some components may display extremely low bioavailability [3, 4]. Thus, they cannot be regarded as the main effective components of Chinese medicine formulae, because efficacy is considered to rely on bioactive compounds with sufficient exposure in the plasma or target organs [5, 6]. Hence, it is necessary to develop a strategy for screening bioactive components with high exposure from Chinese medicine formulae.…”

In Vitro Comparative Study of the Inhibitory Effects of Mangiferin and Its Aglycone Norathyriol towards UDP-Glucuronosyl Transferase (UGT) Isoforms

“…Secondly, the aglycone of MGF, rather than MGF, had the inhibition effect on UGTs, so the metabolism of MGF to NTR should also be considered. In fact, the NTR exposure after oral administration of MGF was extremely slow, and after administration of 200 mg/kg MGF, the concentration and exposure of NTR was quite low (C max < 3 ng/mL), which was lower than that of the parent drug (C max : 202.58 ng/mL) by roughly two orders of magnitude (AUCNTR/AUCMGF < 3%) [ 52 ]. However, given of its slow generation and elimination rates, possible accumulation of NTR in the long term of MGF treatment and exert effects should be considered.…”