Pharmacokinetics of mangiferin and its metabolite—norathyriol, Part 2: Influence of UGT, CYP450, P‐gp, and enterobacteria and the potential interaction in Rhizoma Anemarrhenae decoction with timosaponin B2 as the major contributor

Abstract

The poor bioavailability of mangiferin (MGF) is a major obstacle on its further development. Aimed to illustrate the underlying mechanism and improve its poor exposure, the compared PK profiles of MGF and norathyriol (NTR) after different MGF preparation were performed: pure MGF, the Rhizoma Anemarrhenae (Zhi-mu) decoction, MGF, and timosaponin B2 (TB-2) combination. Furthermore, the potential contributing factors, including uridine diphosphoglucuronosyltransferase (UGT), cytochrome P450 (CYP450), P-gp, and enterobacterial were investigated by comparing the PK profiles with and without the corresponding inhibitors or in different rat models. After taking MGF, CYP450 and UGT inhibition could decrease MGF and NTR exposure; Pgp inhibition slightly enhanced (48%) MGF exposure, whereas more apparent for the improved NTR exposure (302%); enterobacterial inhibition almost completely stopped the NTR production, but no such effect was observed for MGF. Compared with the limited improvement by the abovementioned inhibition, the MGF and NTR exposure could significantly increase by 11.5-and 5.9-fold in the Zhi-mu decoction compared with the MGF treatment, probably contributed to TB-2 as an absorption enhancer because the MGF and TB-2 combination produced a similar level of improvement on the PK paremeters of MGF and NTR to the herb treatment. Likewise, most of the effects by UGT, CYP450, P-gp, and enterobacteria followed a similar variation tendency between them. Therefore, the poor bioavailability of MGF possibly mainly attributed to its poor membrane permeability, but not transporters or metabolic enzymes, and the compatibility of MGF and TB-2 could probably expand the prospective application of MGF by improving its bioavailability. V C 2016 BioFactors, 42(5): [545][546][547][548][549][550][551][552][553][554][555] 2016

Pharmacokinetic Comparisons of Mangiferin and Mangiferin Monosodium Salt in Rat Plasma by UPLC-MS/MS

“…As summarized in Figures 2 and S4, the significant differences were observed between MG and MG-Na in the mean plasma concentration-time curve. e blood concentration of MG is extremely low following oral administration in our study, and its application can be greatly restricted by its poor intestinal absorption [34], and the results are similar to those reported previously [48,49]. It is necessary for drugs to have a certain level of solubility to penetrate biomembranes.…”

“…Several researchers have also reported that the oral bioavailability of mangiferin was extremely low in rats, which has been shown to be as low as 1.2% [50]. e results from Tian et al proved that the poor bioavailability of MG is possibly mainly attributed to its poor solubility and membrane permeability and, however, less correlated with transporters and metabolic enzymes (CYP450) [49]. However, the C max of MG-Na (496.867 ± 79.472 μg/L) was significantly increased by 20.8-fold (P < 0.001) when compared with MG (23.878 ± 4.457 μg/L), which indicated that the absorption of MG-Na was very good in rats in vivo.…”

Monitoring of polyphenol mangiferin by liquid chromatography tandem mass spectrometry in rat and its comparative pharmacokinetic study of a single compound, a single botanic extract and multiple botanic extract

“…The results of this study show that both the single herb of Anemarrhenae Rhizoma extract and multiple botanic SZRD show bioavailability excellence over the pure compound mangiferin after oral administration. The previous published paper mentioned that the pharmacokinetics of mangiferin would be influenced by uridine diphosphoglucuronosyltransferase (UGT), cytochrome P450 (CYP450), P‐glycoprotein (P‐gp), and enterobacteria .…”

“…The results of this study show that both the single herb of Anemarrhenae Rhizoma extract and multiple botanic SZRD show bioavailability excellence over the pure compound mangiferin after oral administration. The previous published paper mentioned that the pharmacokinetics of mangiferin would be influenced by uridine diphosphoglucuronosyltransferase (UGT), cytochrome P450 (CYP450), P-glycoprotein (P-gp), and enterobacteria [20]. In this study, the AUC value and oral bioavailability (0.6%) of the oral administration for the single compound, mangiferin, is significantly lower than that of the single herb and the multiple herbal preparation, which may be due to the poor lipophilicity [10].…”

Exploring and Validating Physicochemical Properties of Mangiferin Through GastroPlus ® Software

“…Mgf, however, encounters numerous challenges when administered orally, principally due to its poor solubility [11], low bioavailability [12], high hepatic first-pass metabolism [13] and high P-gp efflux [14]. Looking into these challenges, the need of the hour is to incorporate Mgf into a delivery system that has distinct potential to improve its bioavailability and, eventually, increase drug levels in systemic circulation.…”