Abstract
Terpene lactones are a class of bioactive constituents of standardized preparations of Ginkgo biloba leaf extract, extensively used as add-on therapies in patients with ischemic cardiovascular and cerebrovascular diseases. This investigation evaluated human pharmacokinetics of ginkgo terpene lactones and impact of their carboxylation in blood. Human subjects received oral YinXing-TongZhi tablet or intravenous ShuXueNing, two standardized ginkgo preparations. Their plasma protein-binding and platelet-activating factor antagonistic activity were assessed in vitro. Their carboxylation was assessed in phosphate-buffered saline (pH 7.4) and in human plasma. After dosing YinXing-TongZhi tablet, ginkgolides A and B and bilobalide exhibited significantly higher systemic exposure levels than ginkgolides C and J; after dosing ShuXueNing, ginkgolides A, B, C, and J exhibited high exposure levels. The compoundsā unbound fractions in plasma were 45ā92%. Apparent oral bioavailability of ginkgolides A and B was mostly >100%, while that of ginkgolides C and J was 6ā15%. Bilobalideās bioavailability was probably high but lower than that of ginkgolides A/B. Terminal half-lives of ginkgolides A, B, and C (4ā7āh) after dosing ShuXueNing were shorter than their respective values (6ā13āh) after dosing YinXing-TongZhi tablet. Half-life of bilobalide after dosing the tablet was around 5āh. Terpene lactones were roughly evenly distributed in various body fluids and tissues; glomerular-filtration-based renal excretion was the predominant elimination route for the ginkgolides and a major route for bilobalide. Terpene lactones circulated as trilactones and monocarboxylates. Carboxylation reduced platelet-activating factor antagonistic activity of ginkgolides A, B, and C. Ginkgolide J, bilobalide, and ginkgo flavonoids exhibited no such bioactivity. Collectively, differences in terpene lactonesā exposure between the two preparations and influence of their carboxylation in blood should be considered in investigating the relative contributions of terpene lactones to ginkgo preparationsā therapeutic effects. The results here will inform rational clinical use of ginkgo preparations.
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Acknowledgements
This work was funded by grants from the Science & Technology Commission of Shanghai Municipality (13DZ1970200), the National Science & Technology Major Project of China āKey New Drug Creation and Manufacturing Programā (2009ZX09304-002 and 2017ZX09301012006), the National Science Foundation of China for Distinguished Young Scholars (30925044) and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12050306).
Author contributions
Participated in research design: CL, LL, Y-hH. Conducted experiments: LL, X-wL, J-lY, WN, W-wJ, QW, X-nD, F-qW, F-fD, C-cZ, Y-fL, FX. Performed data analysis: CL, LL, QG, X-wL. Wrote or contributed to the writing of the manuscript: CL, LL, OEO, X-wL.
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Liu, Xw., Yang, Jl., Niu, W. et al. Human pharmacokinetics of ginkgo terpene lactones and impact of carboxylation in blood on their platelet-activating factor antagonistic activity. Acta Pharmacol Sin 39, 1935ā1946 (2018). https://doi.org/10.1038/s41401-018-0086-7
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DOI: https://doi.org/10.1038/s41401-018-0086-7
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