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
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.
To examine the metabolism of genipin-1-β-d-gentiobioside (GG), its distribution and biotransformation in vivo and in vitro were investigated. Urine, plasma, feces, and various organs were collected after oral administration of GG to normal rats and pseudo-germ-free rats to evaluate GG metabolism in vivo. GG was incubated with intestinal flora and primary hepatocytes in vitro to investigate microbial and hepatic metabolism. Using HPLC-Q-TOF-LC/MS, 11 metabolites of GG were absolutely or tentatively identified in terms possible elemental compositions, retention times, and characteristics of fragmentation patterns corresponding to eight biotransformations: deglycosylation, hydroxylation, sulfate conjugation, glucuronidation, hydrogenation, demethylation, glycosylation, and dehydration. Fewer metabolites were detected in pseudo-germ-free rats than in conventional rats. Moreover, geniposide and genipin were generated by the deglycoslation of intestinal bacteria. Geniposidic acid was detected in rat primary-hepatocyte incubation. This study first explores the metabolism of GG in vivo and in vitro. The results can aid the elucidation of PK profiles and clinical usage of gardenia fruit.
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