Human pharmacokinetics of ginkgo terpene lactones and impact of carboxylation in blood on their platelet-activating factor antagonistic activity

Authors: Xin-wei Liu1,2, Jun-ling Yang1, Wei Niu1, Wei-wei Jia1, Olajide E. Olaleye1, Qi Wen1, Xiao-na Duan1, Yü-hong Huang3, Feng-qing Wang1, Fei-fei Du1, Chen-chun Zhong1, Yan-fen Li3, Fang Xu1, Qi Gao4, Li Li1, Chuan Li1,2
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, Shanghai 201203, China
3 Second Affiliated Hospital, Tianjin University of Traditional Chinese Medicine, Tianjin 300250, China
4 SPH XingLing Science & Technology Pharmaceutical Co., Ltd., Shanghai 201703, China
Correspondence to: Li Li:, Chuan Li:,
DOI: 10.1038/s41401-018-0086-7
Received: 4 April 2018
Accepted: 31 May 2018
Advance online: 27 July 2018


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 plateletactivating 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 compounds’ unbound fractions in plasma were 45–92%. Apparent oral bioavailability of ginkgolides A and B was mostly >100%, while that of ginkgolides C and J was 6–15%. Bilobalide’s bioavailability was probably high but lower than that of ginkgolides A/B. Terminal half-lives of ginkgolides A, B, and C (4–7 h) after dosing ShuXueNing were shorter than their respective values (6–13 h) after dosing YinXing-TongZhi tablet. Half-life of bilobalide after dosing the tablet was around 5 h. 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 lactones’ 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 preparations’ therapeutic effects. The results here will inform rational clinical use of ginkgo preparations.
Keywords: Ginkgo biloba; human pharmacokinetics; renal excretion; terpene lactone; monocarboxylate; platelet-activating factor

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