Systemic and cerebral exposure to and pharmacokinetics of flavonols and terpene lactones after dosing standardized Ginkgo biloba leaf extracts to rats via different routes of administration

Abstract

Background and Purpose Flavonols and terpene lactones are putatively responsible for the properties of Ginkgo biloba leaf extracts that relate to prevention and treatment of cardiovascular disease and cerebral insufficiency. Here, we characterized rat systemic and cerebral exposure to these ginkgo compounds after dosing, as well as the compounds’ pharmacokinetics. Experimental Approach Rats received single or multiple doses of ShuXueNing injection (prepared from GBE50 for intravenous administration) or GBE50 (a standardized extract of G. biloba leaves for oral administration). Brain delivery of the ginkgo compounds was assessed with microdialysis. Various rat samples were analysed using liquid chromatography/mass spectrometry. Key Results Slow terminal elimination features of the flavonols counterbalanced the influence of poor oral bioavailability on their systemic exposure levels, which also resulted in significant accumulation of the compounds in plasma during the subchronic treatment with ShuXueNing injection and GBE50. Unlike the flavonols, the terpene lactones had poor enterohepatic circulation due to their rapid renal excretion and unknown metabolism. The flavonol glycosides occurred as major forms in plasma after dosing with ShuXueNing injection, while the flavonol aglycone conjugates were predominant in plasma after dosing with GBE50. Cerebral exposure was negligible for the flavonols and low for the terpene lactones. Conclusion and Implications Unlike the significant systemic exposure levels, the levels of cerebral exposure to the flavonols and terpene lactones are low. The elimination kinetic differences between the two classes of ginkgo compounds influence their relative systemic exposure levels. The information gained is relevant to linking ginkgo administration to the medicinal effects.

Simultaneous determination by UPLC-MS/MS of seven bioactive compounds in rat plasma after oral administration of Ginkgo biloba tablets: application to a pharmacokinetic study

“…After oral administration of GBTs, terpene lactones were eliminated faster than flavonols. This is consistent with Chen et al (2013). Moreover, the flavonols presented double peaks in curves of mean plasma concentration.…”

Renal Tubular Secretion of Tanshinol: Molecular Mechanisms, Impact on Its Systemic Exposure, and Propensity for Dose-Related Nephrotoxicity and for Renal Herb-Drug Interactions

“…An herbal constituent can be defined as drug-like if it possesses the desired pharmacologic potency, a wide safety margin, appropriate pharmacokinetic (PK) properties, and adequate content in the medicine dosed. Recent multicompound PK studies have indicated that human subjects and laboratory animals are considerably exposed to only a few constituents of an herbal medicine after dosing (Lu et al, 2008;Liu et al, 2009;Li et al, 2012a;Chen et al, 2013;Cheng et al, 2013;Hu et al, 2013;Jiang et al, 2015;Li et al, 2015). Such PK studies provide information for pharmacologists regarding which herbal compounds merit further evaluation.…”

Systemic Exposure to and Disposition of Catechols Derived from Salvia miltiorrhiza Roots (Danshen) after Intravenous Dosing DanHong Injection in Human Subjects, Rats, and Dogs

“…The observed PK interspecies difference should be considered in pharmacological research of DanHong injection. In PK studies of other herbal medicines, significant differences in elimination half-life have also been found to cause considerably different systemic exposure to herbal compounds; long elimination half-life may considerably counterbalance influence of poor oral bioavailability on systemic exposure to an herbal compound Chen et al, 2013;Jiang et al, 2015). With rapidly increasing application of analytical techniques, such as liquid chromatography/mass spectrometry, in research on herbal medicines, content levels of compounds in herbal formulations and their elimination half-lives have become more and more available in literature; such data of herbal compounds could be used together as potential PK marker to predict their systemic exposure after dosing herbal injections.…”

“…Rats were given filtered tap water and commercial rat chow ad libitum and allowed to acclimate to the facilities and environment for 3 days before use. Rats received in-house femoralartery-cannulation for blood sampling or bile duct cannulation for bile sampling (Chen et al, 2013;Cheng et al, 2013). After surgery, rats were housed individually and allowed to regain their preoperative body weights before further use.…”