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

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 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.

Multiple circulating alkaloids and saponins from intravenous Kang-Ai injection inhibit human cytochrome P450 and UDP-glucuronosyltransferase isozymes: potential drug-drug interactions

“…Ginsenosides Rc (D3) and Rb1 (D5) were not detected in bile, and mainly were eliminated through renal excretion. Except the in vivo metabolism, i.e., oxidation and de-glycosylation [16], the delivery to the rat tissues of circulating herbal compounds through blood ow were also an important factor to determine the systemic exposure and excretion of circulating compounds [31]. The V SS values of dosed A3, C6 and C9 were 100.55-220.11 mL/kg, which were near the rat extracellular volume (300 mL/kg) [32], indicating that these herbal compounds could be distributed evenly in various body tissues, except several barriered tissues.…”

High degree of pharmacokinetic compatibility exists between the five-herb medicine XueBiJing and antibiotics comedicated in sepsis care

“…The PKC study first requires identifying both the relevant XueBiJing compounds and antibiotics for the investigation and understanding their pharmacokinetics/disposition and drug interaction liabilities. Although XueBiJing is a complex mixture of constituents, PK research can identify the herbal compounds bioavailable for drug interactions; substantial progresses have recently been made in PK research on such complex herbal medicines33, 34, 35, 38, 48, 49, 50, 51, 52, 53. Twelve herbal compounds (unchanged and metabolized) were tested in this study, the only ones identified in earlier human PK study (despite the high assay sensitivity) from the 104 constituents detected in XueBiJing.…”

Sample Preparation and Bioanalysis Validation for Natural Product Sample

“…Chemically reactive tannins and forming inter-and intra-molecular hydrogen bonds that facilitate can precipitate macromolecules, such as proteins and carbohydrates. For the preparation of penta-O-galloyl--d-glucose samples from tannic acid in the plasma matrix for pharmacokinetic testing the liquid-liquid extraction technique and the incorporation of quantification with reverse-phase HPLC [100].…”

“…Terpene lactone is a class of bioactive constituents of standard preparations of Ginkgo biloba leaf extract, which is widely used as adjunctive therapy in patients with ischemic cardiovascular and cerebrovascular diseases. In a study conducted by this investigation evaluated human pharmacokinetics of lactone terpene ginkgo and the effects of carboxylation in the blood [100]. Ginkgo biloba leaf extract is often used as an herbal medicinal product as a food supplement and cardiovascular treatment [101].…”

“…Preparation of biological samples is used liquid-liquid extraction method with the addition of hydrochloric acid before extraction using ethyl acetate solvent. The extraction product is then dried by nitrogen gas flow and the residual results obtained are dissolved in acetonitrile for analysis by mass spectra [100]. Another study reported on the study of pharmacokinetic evaluations of the main compounds in the dosage formulation of Ginkgo Biloba leaves.…”