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Li X.-J.,University of Sichuan | Li X.-J.,Chengdu BaiKang Institute of Pharmacology and Toxicology | Yang K.,Chengdu BaiKang Institute of Pharmacology and Toxicology | Du G.,Sichuan Provincial Institute for Food and Drug Control | And 2 more authors.
Analytical and bioanalytical chemistry | Year: 2015

A liquid chromatography-mass spectrometry (LC-MS) method coupled with specialized sample-preparation strategies was developed to investigate the hydrolysis of ginkgolide B (GB) in physiological environments in comparison with that of ginkgolide A (GA). The rapid hydrolysis processes were captured by the direct injection of samples prepared in the volatile buffers. The LC-MS behavior of the hydrolyzed products, including three monocarboxylates and three dicarboxylates, was acquired. The monocarboxylates were identified by fragmentation analysis, and the dicarboxylates were accordingly tentatively identified by reaction sequences. The base-catalyzed hydrolysis of GB and GA was characterized at 4 °C within pH 7.0-10.7. The regioselective reactions on the lactone-C and lactone-F were revealed by thermodynamic studies at pH 6.8 and 7.4. It was revealed that the 1-hydroxyl group on the skeleton of GB blocks the reactivity of the lactone-E. On the basis of these results, a distinctive hydrolysis phenomenon of GB was confirmed in plasma of humans, rats, and dogs as a rapid degradation of the trilactone along with the only production of the lactone-F-hydrolyzed product. This phenomenon is also closely associated with the 1-hydroxyl group, because it was not observed in GA. More interestingly, the underlying mechanism was revealed not to be associated with any typical enzyme-catalyzed process, but to be potentially involved with a selective reaction of the intact or broken lactone-C moiety with endogenous small-molecule reactants in plasma. This in-depth knowledge of the hydrolysis of GB versus GA not only facilitated understanding of their pharmacological mechanisms but also provided potential routes to study the structure-activity relationships of ginkgolides. Graphical Abstract Regioselective hydrolysis of ginkgolide B in pH 7.4 buffers and plasma. Source


Li X.-J.,University of Sichuan | Li X.-J.,Chengdu BaiKang Institute of Pharmacology and Toxicology | Yang K.,Chengdu BaiKang Institute of Pharmacology and Toxicology | du G.,Sichuan Provincial Institute for Food and Drug Control | And 3 more authors.
Analytical and Bioanalytical Chemistry | Year: 2015

A liquid chromatography–mass spectrometry (LC–MS) method coupled with specialized sample-preparation strategies was developed to investigate the hydrolysis of ginkgolide B (GB) in physiological environments in comparison with that of ginkgolide A (GA). The rapid hydrolysis processes were captured by the direct injection of samples prepared in the volatile buffers. The LC–MS behavior of the hydrolyzed products, including three monocarboxylates and three dicarboxylates, was acquired. The monocarboxylates were identified by fragmentation analysis, and the dicarboxylates were accordingly tentatively identified by reaction sequences. The base-catalyzed hydrolysis of GB and GA was characterized at 4 °C within pH 7.0–10.7. The regioselective reactions on the lactone-C and lactone-F were revealed by thermodynamic studies at pH 6.8 and 7.4. It was revealed that the 1-hydroxyl group on the skeleton of GB blocks the reactivity of the lactone-E. On the basis of these results, a distinctive hydrolysis phenomenon of GB was confirmed in plasma of humans, rats, and dogs as a rapid degradation of the trilactone along with the only production of the lactone-F-hydrolyzed product. This phenomenon is also closely associated with the 1-hydroxyl group, because it was not observed in GA. More interestingly, the underlying mechanism was revealed not to be associated with any typical enzyme-catalyzed process, but to be potentially involved with a selective reaction of the intact or broken lactone-C moiety with endogenous small-molecule reactants in plasma. This in-depth knowledge of the hydrolysis of GB versus GA not only facilitated understanding of their pharmacological mechanisms but also provided potential routes to study the structure–activity relationships of ginkgolides. [Figure not available: see fulltext.] © 2015 Springer-Verlag Berlin Heidelberg Source


Li X.-J.,University of Sichuan | Li X.-J.,Chengdu BaiKang Institute of Pharmacology and Toxicology | Wang Y.-Q.,Chengdu BaiKang Institute of Pharmacology and Toxicology | Yang J.,University of Sichuan | And 5 more authors.
Analytical and Bioanalytical Chemistry | Year: 2015

Abstract Ginkgolide B (GB) has a unique structure incorporating three γ-lactones that may be hydrolyzed in aquae as carboxylate forms. However, the determinations of them are challenging because there is no way to prepare the standards of any hydrolyzed products of GB in the solid state. In this report, a semi-quantitative method was developed to determine the monocarboxylate forms of GB in plasma. UPLC coupled with selected ion monitoring (SIR) of m/z 423 and m/z 441 were employed to detect the trilactone and monocarboxylates in assistances with the frozen method and the recovered method, which were, respectively, used to stabilize the hydrolyzed states and fully recover the monocarboxylates as the trilactone in samples. Two monocarboxylates were detected in pH 7.4 potassium phosphate buffers (PPB) after incubations, while only one was found in plasma in vitro and in vivo. The identifications of them require further studies. Following the bioanalytical validation of the trilactone, critical issues of the relative responses of the monocarboxylates in contrast to the trilactone, matrix effects, and stabilities were carefully investigated with subtly designed measures. The validation results supported the quantifications of monocarboxylates in PPB or plasma directly by using the corresponding calibration curve of the trilactone. The applications of this method presented a clear disparity between the hydrolysis kinetics of GB in plasma and PPB. Based on the quantification results and method applications, it was concluded that the present method was suitable to study the complex hydrolysis mechanisms of GB in vitro and in vivo. © 2015 Springer-Verlag Berlin Heidelberg. Source

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