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Understanding the regioselective hydrolysis of ginkgolide B under physiological environment based on generation, detection, identification, and semi-quantification of the hydrolyzed products

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Abstract

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.

Regioselective hydrolysis of ginkgolide B in pH 7.4 buffers and plasma

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Acknowledgement

We are grateful for financial support from the NSFC (81302844). We thank Professor M.Z. Liang at West China Hospital (Sichuan University) for gifting human plasma from healthy volunteers.

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The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Key laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Xue-**g Li, Liang Xu & Ke Lan

  2. Chengdu BaiKang Institute of Pharmacology and Toxicology, Chengdu, 610046, China

    Xue-**g Li, Kui Yang & Ke Lan

  3. Sichuan Provincial Institute for Food and Drug Control, Chengdu, 610036, China

    Gang Du

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  1. Xue-**g Li
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  2. Kui Yang
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Correspondence to Ke Lan.

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Li, XJ., Yang, K., Du, G. et al. Understanding the regioselective hydrolysis of ginkgolide B under physiological environment based on generation, detection, identification, and semi-quantification of the hydrolyzed products. Anal Bioanal Chem 407, 7945–7956 (2015). https://doi.org/10.1007/s00216-015-8963-0

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