Pharmacokinetic effects of ginsenoside Rg1 on aconitine, benzoylaconine and aconine by UHPLC–MS/MS

Abstract

Ginseng and aconite are well‐known couplet medicinals. Ginsenoside Rg1 is the main active ingredient in ginseng, and aconitine (AC), benzoylaconine (BAC) and aconine (ACN) are three representative alkaloids in aconite, which belong to the diester alkaloids, monoester alkaloids and alkanolamine alkaloids respectively. The aim of this study was to investigate the pharmacokinetic effects of ginsenoside Rg1 on the three types of alkaloids and to provide evidences for their compatibility mechanism. In this study, the ginsenoside Rg1 was simultaneously intragastrically administered to rats with AC, BAC and ACN, respectively, and the rat plasma was collected at different time points. The plasma drug concentrations of the three types of alkaloids were determined by UHPLC–MS/MS, and the pharmacokinetic parameters were calculated. The results indicated that the peak concentration and area under the concentration–time curve of BAC were significantly increased (P < 0.05), those for AC were decreased (P < 0.05), and the values for ACN did not change after pretreatment with ginsenoside Rg1. It was inferred that ginsenoside Rg1 may affect the absorption and metabolism of AC and BAC and then change their pharmacokinetic parameters. Subsequently, their absorption and metabolism were further investigated using the Caco‐2 cell monolayer and rat liver microsomes in vitro. The Caco‐2 cell monolayer absorption assay indicated that ginsenoside Rg1 could promote the absorption of AC and BAC, and the rat liver microsomes metabolism assay indicated that ginsenoside Rg1 accelerated the metabolism of AC and did not affect the other two alkaloids. All of the results indicated that ginsenoside Rg1 may reduce the toxicity of aconite and improve its efficacy by promoting the absorption of BAC and accelerating the metabolism of AC. These results could provide evidence for the compatibility mechanism of the traditional Chinese herbal formula Shenfu Decoction.

Compatibility of Fuzi and Ginseng Significantly Increase the Exposure of Aconitines

“…Their T 1/2 and AUC 0-t would be significantly increased in Shenfu group ( Table 6 ), which may be caused by the inhibitory of the P-glycoprotein (P-gp)-mediated aconitines efflux by in vivo metabolites of ginsenosides ( Chen et al, 2009 ; Tang et al, 2012 ; Li et al, 2014 ). These phenomena were consistent with Xu’s study ( Xu et al, 2020 ). Among all exposed components, songorine, a non-ester alkaloid with good anti-arrhythmic effects ( Dzhakhangirov et al, 1997 ; Khan et al, 2018 ) and cardioprotection efficacy ( Li et al, 2021 ), showed a larger C max within 1 h, which could effectively eliminate the potential cardiotoxicity of the diester alkaloids (e.g., mesaconitine and hypaconitine).…”

“…However, their AUC 0-t values of Shenfu groups (5.69 for songorine, 8.93 for hypaconitine) were higher than those of Fuzi group (5.56 for songorine, 6.16 for hypaconitine), indicating the hypaconitine and songorine in the Shenfu group was significantly faster than those of Fuzi group in the elimination phase. The main reason might be that the ginsenoside Rg 1 could promote absorption of aconitines ( Xu et al, 2020 ) and up-regulate in vivo expression of CYP450 for accelerating the metabolism of hypaconitine and songorine ( Li et al, 2019 ). The exposure concentrations of other aconitines were higher in Shenfu group, especially for the diester alkaloid (i.e., mesaconitine), monoester alkaloids (i.e., benzoylaconitine, benzoylmesaconitine, and benzoylhypaconitine) ( He et al, 2015 ; Xie et al, 2021 ), and non-ester alkaloids (i.e., aconine and mesaconine).…”

“…In this study, an HPLC-MS/MS method for quantification of 10 aconitines components with all three types of structure in rat plasma was developed ( Figure 1 ). The method had a lower limit of detection (LOD) and limit of quantification (LOQ) than other methods ( Zhang et al, 2014 ; Xu et al, 2020 ). The comparative pharmacokinetic study between Fuzi decoction with ginseng-Fuzi decoction was conducted to screen out the in vivo active components of Shenfu oral prescriptions.…”

“…Currently, the pharmacokinetic studies of aconites were usually reported on Shenfu injection ( Zhang et al, 2008 ; Zhang et al, 2016 ; Shen et al, 2021 ). There is no other relevant study with simultaneous quantification of three types of aconitines for oral preparations containing Fuzi-ginseng herb pair ( Xu et al, 2020 ). Shenfu preparations have been commonly used in the treatment of heart failure, and even the shock patient of severe-stage COVID-19.…”

Cardiac efficacy and toxicity of aconitine: A new frontier for the ancient poison

“…Aconite herbal medicines are frequently formulated with Ginseng, 13,72,73 Glycyrrhiza, 74 and Sweroside, 75,76 Paeoniflorin, 77‐79 Ganjiang, 80‐82 and so forth. Ginsenoside Rg1, the main active ingredient of Ginseng, can alter the pharmacokinetic behavior of AC and accelerate the metabolism of the toxic alkaloid to less toxic monoester alkaloids in the liver 83 . Glycyrrhiza and aconite compatibility alleviates AC‐induced myocardial injuries, since Liquiritin, Glycyrrhetinic Acid, 84 and isoliquiritigenin 85 extracted from Glycyrrhiza not only regulate Ca 2+ homeostasis and inhibit following expressions of proapoptotic proteins 86,87 but also promote detoxification of AC by upregulating Nrf2 signaling pathway and CYP450s 85 .…”