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Featured researches published by Xiaoting Tian.


Drug Metabolism and Disposition | 2014

The hepatobiliary disposition of timosaponin B2 is highly dependent on influx/efflux transporters but not metabolism

Jingjing Sheng; Xiaoting Tian; Guanglin Xu; Zhitao Wu; Chen Chen; Le Wang; Lili Pan; Chenggang Huang; Guoyu Pan

The purpose of this study was to characterize the hepatobiliary disposition of timosaponin B2 (TB-2), a natural saponin. Although TB-2 has multiple pharmacologic activities, the mechanism of its hepatobiliary disposition has not been explored. Because the metabolism of TB-2 is limited and the accumulation of TB-2 in primary hepatocytes is highly temperature dependent (93% of its accumulation is due to active uptake), the contribution of hepatic transporters was investigated. Organic anion-transporting polypeptide (OATP) 1B1– and OATP1B3-transfected human embryonic kidney 293 cells were employed. TB-2 serves as a substrate for OATP1B1 and OATP1B3, with the former playing a predominant role in the hepatic uptake of TB-2. An inhibition study in sandwich-cultured rat hepatocytes suggested that TB-2 is a substrate for both breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2), consistent with its high biliary excretion index (43.1–44.9%). This hypothesis was further verified in BCRP and MRP2 membrane vesicles. The cooperation of uptake and efflux transporters in TB-2 hepatic disposition could partially explain the double-peak phenomenon observed in rat plasma and liver and biliary clearance, which accounted for 70% of the total TB-2 clearance. Moreover, TB-2 significantly increased the rosuvastatin concentration in rat plasma in a concentration-dependent manner and decreased its biliary excretion, which corresponded to reductions in rosuvastatin accumulation in hepatocytes and the biliary excretion index in sandwich-cultured rat hepatocytes, representing a perfect example of a potential saponin-statin drug-drug interaction. These studies demonstrate that transporters (Oatp, Bcrp/Mrp2), but not metabolism, contribute significantly to rat TB-2 hepatobiliary disposition.


Analytical and Bioanalytical Chemistry | 2016

Systematic and comprehensive strategy for metabolite profiling in bioanalysis using software-assisted HPLC-Q-TOF: magnoflorine as an example

Xiaoting Tian; Yucheng Zhang; Zhixiong Li; Pei Hu; Mingcang Chen; Zhaolin Sun; Yunfei Lin; Guoyu Pan; Chenggang Huang

AbstractMetabolite profiling plays a crucial role in drug discovery and development, and HPLC–Q-TOF has evolved into a powerful and effective high-resolution analytical tool for metabolite detection. However, traditional empirical identification is laborious and incomplete. This paper presents a systematic and comprehensive strategy for elucidating metabolite structures using software-assisted HPLC-Q-TOF that takes full advantage of data acquisition, data processing, and data mining technologies, especially for high-throughput metabolite screening. This strategy has been successfully applied in the study of magnoflorine metabolism based on our previous report of its poor bioavailability and drug–drug interactions. In this report, 23 metabolites of magnoflorine were tentatively identified with detailed fragmentation pathways in rat biological samples (urine, feces, plasma, and various organs) after i.p. or i.g. administration, and for most of these metabolites, the metabolic sites were determined. The phase I biotransformations of magnoflorine (M1-M7, M10-M14) consist of demethylation, dehydrogenation, hydroxylation, methylene to ketone transformation, N-ring opening, and dehydroxylation. The phase II biotransformations (M8, M9, and M15-M23) consist of methylation, acetylation, glucuronidation, and N-acetylcysteine conjugation. The results indicate that the extensive metabolism and wide tissue distribution of magnoflorine and its metabolites may partly contribute to its poor bioavailability and drug–drug interaction, and i.p. administration should thus be a suitable approach for isolating magnoflorine metabolites. In summary, this strategy could provide an efficient, rapid, and reliable method for the structural characterization of drug metabolites and may be applicable for general Q-TOF users. Graphical abstractᅟ


Biofactors | 2016

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

Xiaoting Tian; Yu Gao; Zhou Xu; Shan Lian; Yuanjie Ma; Xiaozhen Guo; Pei Hu; Zhixiong Li; Chenggang Huang

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.


Biofactors | 2016

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

Xiaoting Tian; Zhou Xu; Zhixiong Li; Yuanjie Ma; Shan Lian; Xiaozhen Guo; Pei Hu; Yu Gao; Chenggang Huang

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; P‐gp 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.


Journal of Agricultural and Food Chemistry | 2016

Comprehensive Evaluation of the Metabolism of Genipin-1-β-d-gentiobioside in Vitro and in Vivo by Using HPLC-Q-TOF

Pei Jiang; Yuanjie Ma; Yu Gao; Zhixiong Li; Shan Lian; Zhou Xu; Weixin Jiang; Xiaoting Tian; Chenggang Huang

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.


Medicinal Chemistry | 2016

The Pharmacokinetics and Metabolism of Neomangiferin, a Major Bioactive Component in Anemarrhena asphodeloides

Yu Gao; Huihui Liu; Pei Hu; Mingcang Chen; Xiaoting Tian; Zhixiong Li; Chenggang Huang

As a natural derivative of bioactive xanthone mangiferin, neomangiferin exhibits a wide spectrum of bioactivities. However, studies have yet to elucidate the metabolic pathways and pharmacokinetics of orally administered neomangiferin in vivo. In this study, a simple and accurate high-performance liquid chromatography/diode array detector method was developed and validated to simultaneously determine neomangiferin and its active metabolite mangiferin in plasma after oral and intravenous administration of neomangiferin to rats. Chromatographic separation was performed in a C18 column by using water containing 0.1% formic acid-acetonitrile (88:12, v/v) at a flow rate of 0.7 mL/min. The calibration curves of neomangiferin and mangiferin in rat plasma were linear at 150-15000 (r=0.9999) and 50-1500 ng/mL (r=0.9994), respectively. The relative standard deviations of intraday and inter-day precision were below 10.7%, and accuracy ranged from 94.0 to 105.5% for both analytes. Experimental results showed that intravenously and orally administered neomangiferin was partly metabolized into mangiferin. Tmax of neomangiferin and mangiferin was low (0.05 h), and the two components were eliminated at t1/2 of 0.95 and 0.73 h, respectively. Similar to that of mangiferin, the oral bioavailability of neomangiferin was also low (about 0.32%). Thirty-three metabolites were detected and absolutely or tentatively identified on the basis of mass spectral fragmentation pattern and elution order or were confirmed by using available reference standards. Our findings suggested that neomangiferin undergoes rapid and extensive phases I and II metabolic processes, such as deglycosylation, dehydroxylation, methylation, glycosylation, glucuronidation, and sulfation, in rats. In general, the pharmacokinetic and metabolic profiles, including poor bioavailability, high absorption and elimination rates, extensive biotransformation, of neomangiferin are similar to those of mangiferin to some degrees.


Journal of Pharmaceutical and Biomedical Analysis | 2018

Absorption, liver first-pass effect, pharmacokinetics and tissue distribution of calycosin-7-O-ß-d-glucopyranoside (C7G) and its major active metabolite, calycosin, following oral administration of C7G in rats by LC–MS/MS

Xiaoting Tian; Shuoji Chen; Yuanyuan Zhang; Luying Chen; Xiaozhen Guo; Zhou Xu; Huan Liu; Pei Hu; Zhenyuan Chen; Zhixiong Li; Chenggang Huang

Graphical abstract Figure. No Caption available. HighlightsA LC–MS/MS method for determination of C7G and calycosin in different samples.The PK and tissue distribution of C7G and calysoin was conducted on C7G treatments.Liver first‐pass effect were predominant on the poor circulating calycosin levels.Calycosin, but not C7G, elicited high tissue distribution on C7G treatments. ABSTRACT Previously, we discovered calycosin, an extensively distributed metabolite of Calycosin‐7‐O‐ß‐d‐glucopyranoside (C7G), elicited stronger anti‐virus activity than C7G. However, the pharmacokinetics and tissue distribution of C7G and calycosin remained obscure on C7G treatments. In this study, a liquid chromatography–tandem mass spectrometry method was established and validated for the simultaneous determination of C7G and calycosin, and it was applied to the pharmacokinetics and tissue distribution of C7G and calycosin following oral administration of C7G at 120 mg/kg in rats. Consequently, the exposure of C7G and calycosin was both similarly low in the systemic plasma, but the levels of calycosin were 53.5 folds higher than that of C7G in the portal vein plasma, corresponding to the liver extraction ratio (ER) of C7G and calycosin at 0.3% and 98.5% respectively. Therefore, our results revealed that liver first‐pass effect played the predominant role in the poor circulating levels of calycosin on C7G treatments, whereas the intestinal first‐pass effect was predominant for those of C7G. In contrast to no observation of C7G, the calycosin levels were 212.1, 30.5 and 4.7 folds higher in the liver, kidney and heart than its circulating levels, respectively. The high tissue distribution of calycosin provided new hints and evidences to the pharmacological mechanisms of C7G and Astragali Radix.


Journal of Chromatography B | 2018

Simultaneous determination of eight bioactive compounds by LC-MS/MS and its application to the pharmacokinetics, liver first-pass effect, liver and brain distribution of orally administrated Gouteng-Baitouweng (GB) in rats

Xiaoting Tian; Zhou Xu; Mingcang Chen; Pei Hu; Fang Liu; Zhaolin Sun; Huan Liu; Xiaozheng Guo; Zhixiong Li; Chenggang Huang

Only focusing on the circulating levels is insufficient for the comprehensive understanding of the physiological disposition of herbal medicine in vivo. Therefore, we conducted the comprehensive investigation on the in vivo dynamic process of orally administrated Gouteng-Baitouweng (GB), a classical herb pair with anti-Parkinson potentials. Serving as the technical base, a sensitive and selective liquid chromatography-tandem mass spectrometry method was established and validated in the plasma, liver and brain, for simultaneous determination of five alkaloids (rhynchophylline, isorhynchophylline, corynoxeine, isocorynoxeine and geissoschizine methyl ether) and three saponins (anemoside B4, anemoside A3 and 23-hydroxybetulinic acid). Following liquid-liquid extraction, favorable chromatographic behaviors of eight analytes were obtained on Waters Xbrigde C18 column within 13 min. This method elicited good linearity for the analytes at the concentration range of 0.3-1000 or 1.8-6000 ng/mL with favorable precision, accuracy and stability. Following oral administration of GB (25 g/kg) in rats, this method was applied to the quantitative analysis in the portal vein plasma, liver, systemic plasma, and brain. Consequently, anemoside B4 was of the highest exposure, followed by 23-hydroxybetulinic acid, anemoside A3, rhynchophylline and isocorynoxeine in vivo. Notably, three saponins were all observed with certain exposure in the brain, along with rhynchophylline at low levels. Besides, five alkaloids and 23-hydroxybetulinic acid underwent serious liver first-pass effect. Hence, the pharmacokinetics, liver first-pass effect, liver and brain distribution of ingredients in GB were clarified, which laid a solid foundation for interpreting its efficacy and safety.


Journal of Agricultural and Food Chemistry | 2018

Absorption, metabolism, and pharmacokinetics profiles of norathyriol, an aglycone of mangiferin, in rats by HPLC-MS/MS

Xiaozhen Guo; Mingcang Chen; Pei Hu; Zhangpeng Shi; Shuoji Chen; Huan Liu; Haoyun Shi; Zhou Xu; Xiaoting Tian; Chenggang Huang

Norathyriol, an aglycone of mangiferin, is a bioactive tetrahydroxyxanthone present in mangosteen and many medicinal plants. However, the biological fate of norathyriol in vivo remains unclear. In this study, the absorption and metabolism of norathyriol in rats were evaluated through HPLC-MS/MS. Results showed that norathyriol was well absorbed, as indicated by its absolute bioavailability of 30.4%. Besides, a total of 21 metabolites of norathyriol were identified in rats, including methylated, glucuronidated, sulfated and glycosylated conjugates, which suggested norathyriol underwent extensive phase II metabolism. Among those metabolites, 15 metabolites were also identified in hepatocytes incubated with norathyriol, indicating the presence of hepatic metabolism. Furthermore, glucuronide and sulfate conjugates, rather than their parent compound, were found to be the main forms existing in vivo after administration of norathyriol, as implicated by the great increase of exposure of norathyriol determined after hydrolysis with β-glucuronidase and sulfatase. The information obtained from this study contributes to better understanding of the pharmacological mechanism of norathyriol.


Biomedical Chromatography | 2018

A sensitive HPLC-MS/MS method for the simultaneous determination of Anemoside B4, Anemoside A3 and 23-hydroxybetulinic acid: application to the pharmacokinetics and liver distribution of Pulsatilla chinensis saponins

Xiaozhen Guo; Yang Xie; Shan Lian; Zhixiong Li; Yu Gao; Zhou Xu; Pei Hu; Mingcang Chen; Zhaolin Sun; Xiaoting Tian; Chenggang Huang

Pulsatilla chinensis saponins, the major active components in the herb, have drawn great attention as potential hepatitis B virus infection and hepatoma treatments. Here, a sensitive and accurate HPLC-MS/MS method was established for simultaneous determination of three saponins - anemoside B4, anemoside A3 and 23-hydroxybetulinic acid - in rat plasma and liver, and fully validated. The method was successfully applied to a pharmacokinetics and liver distribution study of P. chinensis saponins. Consequently, 23-hydroxybetulinic acid, with an extremely low content in the P. chinensis saponins, exhibited the highest exposure in the liver and in sites before and after hepatic disposition, namely, in the portal vein plasma and systemic plasma, followed by anemoside B4, which showed the highest content in the herb, whereas anemoside A3 displayed quite limited exposure. The hepatic first-pass effects were 71% for 23-hydroxybetulinic acid, 27% for anemoside B4 and 37% for anemoside A3, corresponding to their different extents of liver distribution. To our knowledge, this is the first investigation on the liver first-pass effect and distribution of P. chinensis saponins to date. These results also provide valuable information for the understanding of the pharmacological effect of P. chinensis saponins on liver diseases.

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Chenggang Huang

Chinese Academy of Sciences

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Zhixiong Li

Chinese Academy of Sciences

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Pei Hu

Chinese Academy of Sciences

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Zhou Xu

Chinese Academy of Sciences

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Mingcang Chen

Chinese Academy of Sciences

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Xiaozhen Guo

Chinese Academy of Sciences

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Yu Gao

Chinese Academy of Sciences

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Huan Liu

Chinese Academy of Sciences

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Shan Lian

Harbin University of Commerce

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Zhaolin Sun

Chinese Academy of Sciences

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