Simultaneous Evaluation of the Influence of <i>Panax ginseng</i> on the Pharmacokinetics of Three Diester Alkaloids after Oral Administration of Aconiti Lateralis Radix in Rats Using UHPLC/QQQ‐MS/MS

Yang, Liang; Wang, Yuguang; Huang, Guang-yao; Li, Jian; Zhang, Zhaoyan; Gao, Yue

doi:10.1155/2018/6527549

Cited by 6 publications

(6 citation statements)

References 42 publications

(39 reference statements)

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“…The results are shown in Figure 2, indicating that there is no obvious system residual with this method. Compared with other methods, the analysis time was shorter and the extraction method was simpler in our research (Ouyang et al, 2018;Yang et al, 2018).…”

Section: Selectivitymentioning

confidence: 77%

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

Yang

Liang

et al. 2020

Biomedical Chromatography

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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.

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Section: Selectivitymentioning

confidence: 77%

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

Yang

Liang

et al. 2020

Biomedical Chromatography

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“…In our previous study, we had suggested that P. ginseng can inhibit the clearance of aconitine, mesaconitine, and hypaconitine in rats. This results in the fact that the accumulation of aconitine, mesaconitine, and hypaconitine within the body may be the basis of DDI between P. ginseng and Aconiti Lateralis Radix [33].…”

Section: Discussionmentioning

confidence: 99%

Panax ginseng Inhibits Metabolism of Diester Alkaloids by Downregulating CYP3A4 Enzyme Activity via the Pregnane X Receptor

Yang

Wang

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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To investigate the effects of P. ginseng C.A. Mey (P. ginseng) on the metabolism of diester alkaloids and explore the potential mechanism. P. ginseng was administered orally to rats for 7 days, after which liver microsome samples were prepared and then incubated with diester alkaloids. Ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry was used to determinate the concentration of diester alkaloids to calculate the clearance rate. The cocktail method was used to evaluate the effects of oral administration of P. ginseng extracts on the activities of cytochrome P450 (CYP) isoforms in rats through the changes in the pharmacokinetic parameters of the probe drugs. The protein and gene expression of CYP3A2 and pregnane X receptor (PXR) in rats were evaluated by western blotting and quantitative PCR. The specific enzyme inhibitor method and human recombinant enzyme method were used to identify the involvement of sub-CYPs in the metabolism of diester alkaloids in human liver microsomes (HLMs). The clearances of aconitine, mesaconitine, and hypaconitine in the P. ginseng groups were lower than those of the control group. The areas under the curve of midazolam were 2.37 ± 1.05, 4.96 ± 0.51, and 6.23 ± 1.30 mg·L−1·h for the low-, medium-, and high-dose P. ginseng groups, respectively, which were higher than that of the control (2.23 ± 0.64 mg·L−1·h). The clearances of midazolam for the medium- (1.87 ± 0.16 L·h−1·kg−1) and high-dose (1.60 ± 0.34 L·h−1·kg−1) P. ginseng groups were lower than that of the control group (4.66 ± 1.43 L·h−1·kg−1). After exposure to P. ginseng extracts, the gene and protein expression levels of CYP3A4 and PXR were decreased. The hepatic metabolism rates of aconitine, mesaconitine, and hypaconitine in HLMs were decreased to 60.37%, 21.67%, and 10.11%, respectively, when incubated with ketoconazole, a specific inhibitor for CYP3A. The kinetic plots indicated that the KM and Vmax values of CYP3A4 were 10.08 ± 3.26 μM and 0.12 ± 0.01nmol·mg protein−1·min−1 for aconitine, 131.3 ± 99.75 μM and 0.73 ± 0.44 nmol·mg protein−1·min−1 for mesaconitine, and 17.05 ± 9.70 μM and 0.16 ± 0.04 nmol·mg protein−1·min−1 for hypaconitine, respectively. The in vitro mean intrinsic clearance rates by CYP3A4 were 0.0119, 0.0056, and 0.0091 mL·nmol CYP−1·min−1 for aconitine, mesaconitine, and hypaconitine, respectively. Therefore we implied that P. ginseng inhibited the metabolism of diester alkaloids in vitro and decreased the CYP3A4 enzyme activity as well as the gene and protein expression of CYP3A4 and PXR in vivo. CYP3A4 had a larger effect on diester alkaloid metabolism than the other human CYP isoforms, CYP1A2, CYP2C9, and CYP2E1.

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“…In vitro experiment has shown that Ginseng could reduce the metabolism of DDAs through inhibition of CYP3A4 expression and activity [ 79 ]. In a rat model, Ginseng could slow down the metabolisms of DDAs from Fuzi when given orally [ 80 ]. Ginseng combines with Fuzi could increase SOD activity and reduce malondialdehyde (MDA), nitrogen oxide and lactate dehydrogenase, which could enhance cardiac cell viability [ 81 ].…”

Section: Detoxification Of Aconitum In Traditional and Modern Waysmentioning

confidence: 99%

Section: Ginsengmentioning

confidence: 99%

The toxicology and detoxification of Aconitum: traditional and modern views

2021

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Aconitum carmichaeli Debx.-derived herbal medicine has been used for anti-inflammation and anti-arrhythmia purpose for more than two thousand years. It is processed into Chuanwu (Radix Aconiti praeparata) and Fuzi (Radix Aconiti lateralis praeparata) in Traditional Chinese Medicine, which are two useful drugs but with toxic properties. There have been patients poisoned by accidental ingestion of Aconitum plants or misuse of the herbal drug, and this is of great concern to study in-depth. In this review, we provided the traditional and contemporary practice of using Aconitum herbs as medicine, from functions, processing methods to toxicity in ethnomedicine aspects to discuss the underlying connections of traditional and modern understanding on the toxicity of Aconitum plants. We summarized the functions and toxicology of the herbal drugs are analyzed from chemical and clinical aspects, with the help of traditional and modern knowledge of medicine. The medicinal doses and lethal doses determined by researches are summarized, and the usage and processing methods are updated and reviewed in the modern view. In addition, clinical management of poisoned cases using western medicine is discussed. This review provides insights and awareness of safety when using Aconitum-derived herbal medicine, and the application of modern scientific knowledge to optimize the detoxification processes. We suggest the possibility to renew the current standard processing method from the official Pharmacopoeia all over the world.

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Simultaneous Evaluation of the Influence of Panax ginseng on the Pharmacokinetics of Three Diester Alkaloids after Oral Administration of Aconiti Lateralis Radix in Rats Using UHPLC/QQQ‐MS/MS

Cited by 6 publications

References 42 publications

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

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

Panax ginseng Inhibits Metabolism of Diester Alkaloids by Downregulating CYP3A4 Enzyme Activity via the Pregnane X Receptor

The toxicology and detoxification of Aconitum: traditional and modern views

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