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1.
J Ethnopharmacol ; 246: 112243, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31541722

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Ginkgo biloba leaves and Panax ginseng are Chinese medicine commonly used in combination for cerebral disease. AIM OF THE STUDY: To investigate the effect of standard extract of Ginkgo biloba leaves (EGb) on facilitating brain uptake of ginsenoside and its underlying mechanisms. MATERIALS AND METHODS: The increasing uptake of ginsenosides in the brain of rats by EGb were detected by LC-MS/MS analysis. Evans blue and FITC-dextran leakage were determined to evaluate blood-brain barrier (BBB) permeability in vivo. Transendothelial electrical resistance (TEER) and Na-F penetration rate were measured with a co-culture of the human cerebral microvascular endothelial cell line (hCMEC/D3) and human normal glial cell line (HEB) in vitro BBB model. WB were used to analyzed the expression of BBB tight junctions (TJs) related protein (ZO-1, Occludin, Claudin-3, p-ERM, and p-MLC), ultrastructure of TJs was determined by transmission electron microscope. RESULTS: LC-MS/MS analysis demonstrated that EGb could improve brain uptake of ginsenoside Rg1, Re, Rd and Rb1. In vivo study showed that, BBB permeability was significantly increased after EGb administration, evidenced by the markedly increased penetration of FITC-dextran and Evans Blue into the mice brain parenchyma. In the in vitro BBB model, reduced TEER and increased Na-F penetration rate was observed in EGb group, which was associated with alteration of TJs ultrastructure. Furthermore, the expression of p-ERM and p-MLC in hCMEC/D3 as well as mice brain microvessels were significantly upregulated, but no significant change on the expression of TJs proteins (ZO-1, Occludin and Claudin-3). Moreover, the effect of EGb on in vitro BBB permeability and ERM, MLC phosphorylation was counteracted by DPCPX, an A1 adenosine receptor (A1R) antagonist. CONCLUSIONS: EGb might induce ERM/MLC phosphorylation and increase the cell-cell junction gaps to cause a reversible increase of the BBB permeability via A1R signaling pathway. Our results may contribute to better use of EGb in the treatment of brain diseases.


Assuntos
Agonistas do Receptor A1 de Adenosina/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Ginsenosídeos/farmacocinética , Extratos Vegetais/farmacologia , Receptor A1 de Adenosina/metabolismo , Animais , Linhagem Celular , Relação Dose-Resposta a Droga , Ginsenosídeos/metabolismo , Masculino , Camundongos , Extratos Vegetais/administração & dosagem , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos
2.
Artigo em Inglês | MEDLINE | ID: mdl-31877430

RESUMO

The aim of this study was to investigate the synergistic effect and underlying mechanism of compatibility of Aconiti Lateralis Radix Praeparata water-soluble alkaloids (FWA) and Ginseng Radix et Rhizoma total ginsenosides (RTG) on propafenone hydrochloride induced acute heart failure (AHF) rats. Firstly, hemodynamics and serum biochemical indexes were measured to observe the therapeutic effect of FWA, RTG and their compatibility on AHF rats. Non-target serum metabolomics and multicomponent pharmacokinetic experiments were then performed to reveal the mechanism from the two aspects of body reaction and drug behavior in vivo. Data showed the haemodynamics indexes (maximum change rate of left ventricular pressure, heart rate) and neuroendocrine cytokines (TNF-α and Nt-proBNP) levels in rats treated by compatibility of FWA and RTG were improved more significantly than that treated by single drug. Through metabolomics analysis, six metabolites, including L-pipecolic acid, L-arginine, uric acid, N-benzoylglycine, sphingosine-1-phosphate and phosphatidylinositol lyso 16:0, were selected and identified as the potential biomarkers of the synergistic effect. Furthermore, lysine degradation, arginine and proline metabolism, purine metabolism, sphingolipid metabolism, etc. were the differential pathways involved. The results of pharmacokinetics showed Cmax, AUClast and t1/2 of the four components (uracil, salsolinol, guanosine, higenamine) of FWA in compatibility group were obviously higher than that in single drug group, which indicated the absorption and bioavailability of these alkaloids were increased, and the residence time was prolonged after FWA combined with RTG. In conclusion, the therapeutic effect of FWA-RTG on AHF rats was enhanced and that might because the compatibility of FWA-RTG affected the process of some metabolites in AHF rats, and pharmacokinetic behavior of components in FWA was obviously influenced after co-administered with RTG.


Assuntos
Aconitum/química , Alcaloides , Ginsenosídeos , Insuficiência Cardíaca/metabolismo , Panax/química , Alcaloides/farmacocinética , Alcaloides/farmacologia , Animais , Sinergismo Farmacológico , Ginsenosídeos/farmacocinética , Ginsenosídeos/farmacologia , Coração/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Metabolômica , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley
3.
Biomed Chromatogr ; 33(11): e4670, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31368122

RESUMO

Notoginsenoside R1 (NGR1 ), a diagnostic protopanaxatriol-type (ppt-type) saponin in Panax notoginseng, possesses potent biological activities including antithrombotic, anti-inflammatory, neuron protection and improvement of microcirculation, yet its pharmacokinetics and metabolic characterization as an individual compound remain unclear. The aim of this study was to investigate the exposure profile of NGR1 in rats after oral and intravenous administration and to explore the metabolic characterization of NGR1 . A simple and sensitive ultra-fast liquid chromatographic-tandem mass spectrometric method was developed and validated for the quantitative determination of NGR1 and its major metabolites, and for characterization of its metabolic profile in rat plasma. The blood samples were precipitated with methanol, quantified in a negative multiple reaction monitoring mode and analyzed within 6.0 min. Validation parameters (linearity, precision and accuracy, recovery and matrix effect, stability) were within acceptable ranges. After oral administration, NGR1 exhibited dose-independent exposure behaviors with t1/2 over 8.0 h and oral bioavailability of 0.25-0.29%. A total of seven metabolites were characterized, including two pairs of epimers, 20(R)-notoginsenoside R2 /20(S)-notoginsenoside R2 and 20(R)-ginsenoside Rh1 /20(S)-ginsenoside Rh1 , with the 20(R) form of saponins identified for the first time in rat plasma. Five deglycometabolites were quantitatively determined, among which 20(S)-notoginsenoside R2 , ginsenoside Rg1 , ginsenoside F1 and protopanaxatriol displayed relatively high exploration, which may partly explain the pharmacodynamic diversity of ginsenosides after oral dose.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ginsenosídeos/sangue , Ginsenosídeos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Intravenosa , Administração Oral , Animais , Ginsenosídeos/administração & dosagem , Ginsenosídeos/química , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos
4.
Molecules ; 24(16)2019 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-31426477

RESUMO

Ginsenoside Ro (Ro), a major saponin derived and isolated from Panax ginseng C.A. Meyer, exerts multiple biological activities. However, the anti-tumour efficacy of Ro remains unclear because of its poor in vitro effects. In this study, we confirmed that Ro has no anti-tumour activity in vitro. We explored the anti-tumour activity of Ro in vivo in B16F10 tumour-bearing mice. The results revealed that Ro considerably suppressed tumour growth with no significant side effects on immune organs and body weight. Zingibroside R1, chikusetsusaponin IVa, and calenduloside E, three metabolites of Ro, were detected in the plasma of Ro-treated tumour-bearing mice and showed excellent anti-tumour effects as well as anti-angiogenic activity. The results suggest that the metabolites play important roles in the anti-tumour efficacy of Ro in vivo. Additionally, the haemolysis test demonstrated that Ro has good biocompatibility. Taken together, the findings of this study demonstrate that Ro markedly suppresses the tumour growth of B16F10-transplanted tumours in vivo, and its anti-tumour effects are based on the biological activity of its metabolites. The anti-tumour efficacy of these metabolites is due, at least in part, to its anti-angiogenic activity.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ginsenosídeos/farmacologia , Melanoma Experimental/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Saponinas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/farmacocinética , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Biotransformação , Ginsenosídeos/metabolismo , Ginsenosídeos/farmacocinética , Hemólise/efeitos dos fármacos , Melanócitos/efeitos dos fármacos , Melanócitos/patologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Transplante de Neoplasias , Ácido Oleanólico/metabolismo , Ácido Oleanólico/farmacocinética , Ácido Oleanólico/farmacologia , Panax/química , Extratos Vegetais/química , Saponinas/metabolismo , Saponinas/farmacocinética , Neoplasias Cutâneas/patologia
5.
Molecules ; 24(14)2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31323835

RESUMO

We aimed to develop a sensitive method for detecting 13 ginsenosides using liquid chromatography-tandem mass spectrometry and to apply this method to pharmacokinetic studies in human following repeated oral administration of red ginseng extract. The chromatograms of Rb1, Rb2, Rc, Rd, Re, Rf, Rg1, Rg3, Rh2, F1, compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT) in human plasma were well separated. The calibration curve range for 13 ginsenosides was 0.5-200 ng/mL and the lower limit of quantitation was 0.5 ng/mL for all ginsenosides. The inter- and intra-day accuracy, precision, and stability were less than 15%. Among the 13 ginsenosides tested, nine ginsenosides (Rb1, Rb2, Rc, Rd, Rg3, CK, Rh2, PPD, and PPT) were detected in the human plasma samples. The plasma concentrations of Rb1, Rb2, Rc, Rd, and Rg3 were correlated with the content in red ginseng extract; however, CK, Rh2, PPD, and PPT were detected although they are not present in red ginseng extract, suggesting the formation of these ginsenosides through the human metabolism. In conclusion, our analytical method could be effectively used to evaluate pharmacokinetic properties of ginsenosides, which would be useful for establishing the pharmacokinetic-pharmacodymic relationship of ginsenosides as well as ginsenoside metabolism in humans.


Assuntos
Ginsenosídeos/sangue , Ginsenosídeos/química , Panax/química , Extratos Vegetais/sangue , Extratos Vegetais/química , Ginsenosídeos/farmacocinética , Humanos , Redes e Vias Metabólicas , Estrutura Molecular , Extratos Vegetais/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
6.
AAPS PharmSciTech ; 20(6): 252, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300965

RESUMO

The objective of the present study was to investigate the effect of partially hydrolyzed ginsenoside on the physicochemical properties and in vitro release of curcumin from phospholipid-based nanostructured lipid carrier (NLC). NLC formulas modified with partially hydrolyzed ginsenoside (NLC-PG) were prepared with different amounts of ginsenoside using the conventional hot-melt method. The average particle size of curcumin-loaded NLC-PG ranged from 150 to 200 nm, and polydispersity index was in the range of 0.101-0.177, indicating monodispersed particle size distribution. Optical microscopy showed no sedimentation or recrystallization of curcumin even at 10,000 µg/ml concentration as NLC-PG in distilled water, indicating significantly enhanced solubility. TEM image showed that the nanoparticles were monodispersed with a multilayered core/shell structure. X-ray diffraction and FTIR spectroscopy showed that curcumin was amorphous in the NLC-PG, and there was no interaction between curcumin and the excipients. In vitro release study using simulated gastric/intestinal fluid media revealed that the release rate (Jss) of curcumin from the NLC-PG increased as a function of the ginsenoside content in the lipid carrier. Moreover, the Jss of curcumin kept gradually increasing in the presence of lipase, whereas in the presence of viscozyme, it sharply increased until the ginsenoside content reached 9.09% and subsequently plateaued. Partially hydrolyzed ginsenoside increased the Jss of curcumin from curcumin-loaded NLC-PG and therefore may be useful for improving the bioavailability of curcumin.


Assuntos
Curcumina/química , Portadores de Fármacos/química , Ginsenosídeos/química , Lipídeos/química , Nanoestruturas/química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Curcumina/farmacocinética , Portadores de Fármacos/farmacocinética , Excipientes/química , Excipientes/farmacocinética , Ginsenosídeos/farmacocinética , Hidrólise , Lipídeos/farmacocinética , Lisofosfatidilcolinas/química , Lisofosfatidilcolinas/farmacocinética , Tamanho da Partícula , Fosfatidilcolinas/química , Fosfatidilcolinas/farmacocinética , Óleo de Soja/química , Óleo de Soja/farmacocinética , Difração de Raios X/métodos
7.
Acta Pharmacol Sin ; 40(10): 1351-1363, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31358899

RESUMO

XueShuanTong, a lyophilized extract of Panax notoginseng roots (Sanqi) for intravenous administration, is extensively used as add-on therapy in the treatment of ischemic heart and cerebrovascular diseases and comprises therapeutically active ginsenosides. Potential for XueShuanTong-drug interactions was determined; the investigation focused on cytochrome P450 (CYP)3A induction and organic anion-transporting polypeptide (OATP)1B inhibition. Ginsenosides considerably bioavailable for drug interactions were identified by dosing XueShuanTong in human subjects and their interaction-related pharmacokinetics were determined. The CYP3A induction potential was determined by repeatedly dosing XueShuanTong for 15 days in human subjects and by treating cryopreserved human hepatocytes with circulating ginsenosides; midazolam served as a probe substrate. Joint inhibition of OATP1B by XueShuanTong ginsenosides was assessed in vitro, and the data were processed using the Chou-Talalay method. Samples were analyzed by liquid chromatography/mass spectrometry. Ginsenosides Rb1, Rd, and Rg1 and notoginsenoside R1 were the major circulating XueShuanTong compounds; their interaction-related pharmacokinetics comprised compound dose-dependent levels of systemic exposure and, for ginsenosides Rb1 and Rd, long terminal half-lives (32‒57 and 58‒307 h, respectively) and low unbound fractions in plasma (0.8%‒2.9% and 0.4%‒3.0%, respectively). Dosing XueShuanTong did not induce CYP3A. Based on the pharmacokinetics and inhibitory potency of the ginsenosides, XueShuanTong was predicted to have high potential for OATP1B3-mediated drug interactions (attributed chiefly to ginsenoside Rb1) suggesting the need for further model-based determination of the interaction potential for XueShuanTong and, if necessary, a clinical drug interaction study. Increased awareness of ginsenosides' pharmacokinetics and XueShuanTong-drug interaction potential will help ensure the safe use of XueShuanTong and coadministered synthetic drugs.


Assuntos
Citocromo P-450 CYP3A/biossíntese , Medicamentos de Ervas Chinesas/farmacocinética , Ginsenosídeos/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Raízes de Plantas/química , Administração Intravenosa , Adulto , Cromatografia Líquida , Composição de Medicamentos , Interações de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Feminino , Ginsenosídeos/administração & dosagem , Ginsenosídeos/química , Voluntários Saudáveis , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Espectrometria de Massas , Conformação Molecular , Adulto Jovem
8.
J Pharm Biomed Anal ; 174: 367-375, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31202879

RESUMO

Fufang Danshen Dripping Pill (FDDP) and Clopidogrel Bisulfate Tablet (CBT) are usually combined for treatment of coronary artery diseases in clinical. To investigate the pharmacokinetic interaction between FDDP and CBT after oral administration of FDDP, CBT and their combination in rats, a novel LC-MS method with segmented scan modes (multiple reaction monitoring and selected ion monitoring) and polarity (positive and negative ionization) was developed. Clopidogrel and the main active ingredients of FDDP, with different chemical and ionization properties, were simultaneously quantified in plasma in a single run. The method was validated in terms of specificity, linearity, precision, accuracy, recovery, matrix effect and stability. As a result, co-administration of FDDP and CBT significantly altered the pharmacokinetic parameters of danshensu, ginsenoside Rb1, dihydrotanshinone I, tanshinone I and tanshinone IIA of FDDP, as well as clopidogrel. Mechanism studies suggested that induction of liver cytochrome P450 isozymes CYP2C11 and CYP3A1 by co-administration, as well as inhibition of carboxyl esterase 1, was partly responsible for FDDP-CBT pharmacokinetic interactions. The developed LC-MS method could be used to simultaneously quantify different types of in vivo analytes in a single run, and the results could be used for clinical medication guidance of FDDP and CBT.


Assuntos
Clopidogrel/farmacocinética , Medicamentos de Ervas Chinesas/farmacocinética , /farmacocinética , Administração Oral , Animais , Hidrocarboneto de Aril Hidroxilases/metabolismo , Cromatografia Líquida , Citocromo P-450 CYP3A/metabolismo , Família 2 do Citocromo P450/metabolismo , Ginsenosídeos/farmacocinética , Lactatos/farmacocinética , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Esteroide 16-alfa-Hidroxilase/metabolismo , Espectrometria de Massas em Tandem
9.
Biomed Chromatogr ; 33(9): e4580, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31077415

RESUMO

Ginsenoside Rk1 (Rk1) exhibited various potent biological activities. However, its pharmacokinetic profile in vivo remains unclear. In the present study, a simple and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for determination of Rk1 in rat plasma and applied in a pharmacokinetic study. The sample was precipitated with acetonitrile and separated on a Zorbax Eclipse XDB C18 column (50 × 2.1 mm, 1.8 µm). The mobile phase was composed of 0.1% formic acid in water and acetonitrile at a flow rate of 0.4 mL/min. Rk1 and internal standard (ginsenoside Rg3) were quantitatively monitored with precursor-to-product ion transitions of m/z 765.4 → 441.5 and m/z 783.5 → 621.4, respectively. The assay was linear over the concentration range of 5-1000 ng/mL (r > 0.99) with the LLOQ of 5 ng/mL. Other parameters including intra- and inter-day precision and accuracy, extraction recovery and matrix effect were within the acceptable limits. The analyte was stable under the tested storage conditions. The validated method has been successfully applied to a pharmacokinetic study of Rk1 in rat plasma after intravenous (5 mg/kg) and oral (25 mg/kg, 50 mg/kg) administration. After oral administration, Rk1 could be detected in blood at 30 min and reached the highest concentration at 4.29~4.57 h. Our results demonstrated that Rk1 showed low clearance, moderate half-life (3.09-3.40 h) and low bioavailability (2.87-4.23%). The study will provide information for the further application of Rk1.


Assuntos
Cromatografia Líquida/métodos , Ginsenosídeos/sangue , Ginsenosídeos/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Disponibilidade Biológica , Ginsenosídeos/administração & dosagem , Ginsenosídeos/química , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos
10.
Pharmacology ; 104(1-2): 7-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30947229

RESUMO

BACKGROUND: Ocotillol, RT5 and F11, the main active components of ocotillol type ginsenosides, have attracted a lot of attention due to their beneficial effects on neurodegenerative disease models of Alzheimer's disease. Pharmacokinetic (PK) is a bridge linking the herbal medicines and their pharmacological responses. However, few data are available regarding PK behaviors of ocotillol type ginsenosides. METHODS: The liquid chromatography-tandem mass spectrometry methods were developed and validated to calculate the concentrations of 3 ginsenosides in different biological matrices. Rat and beagle dog plasma samples were deproteinized with methanol and separated on Shim-pack GIST C18 column. All of the analytes were detected in positive ion mode using multiple reaction monitoring. RESULTS: The methods showed good linearity (r > 0.996) in the established concentration range. All validated data, such as specificity, intra- and inter-day precision, accuracy, extraction recovery, matrix effect, and stability were within required limits. The values of Cmax and AUC(0-t) indicated ocotillol type ginsenosides had low systemic exposure and poor absorption into blood. T1/2 and MRT(0-t) demonstrated the elimination process of ocotillol type ginsenosides might be slow. Double peaks were observed in the mean plasma concentration versus time profiles of ocotillol, RT5, and F11 after oral intake. CONCLUSIONS: This was the first PK investigation of the ocotillol type ginsenosides in rats and beagle dogs. The results we found here were helpful to our understanding of the absorption mechanism of ocotillol type ginsenosides and provided the scientific basis for further pre-clinical research.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ginsenosídeos/farmacocinética , Fármacos Neuroprotetores/farmacocinética , Panax/química , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/métodos , Cães , Avaliação Pré-Clínica de Medicamentos , Feminino , Ginsenosídeos/administração & dosagem , Masculino , Fármacos Neuroprotetores/administração & dosagem , Ratos , Padrões de Referência , Reprodutibilidade dos Testes , Distribuição Tecidual
11.
Phytomedicine ; 59: 152896, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30978649

RESUMO

BACKGROUND: The selection of active compounds for the quality evaluation of traditional Chinese medicine (TCM), specifically complex formulas, remains a challenge for researchers, as components selected as indexes usually have no clear relation with the therapeutic effects of interest. As a suggested resolution, quality control markers (Q-markers) showed good perspective for discriminating numerous compounds found for specific efficacies. In the presented study, the components of the Yinlan (YL) capsule, a TCM patent formula comprising four ingredients, were evaluated and selected for their lipid regulatory effects using principles for Q-marker selection. PURPOSE: The mechanism of TCM therapeutic effects involves several pathways and targets that combine to become an integrated action in the body. Therefore, it is assumed that specific compounds in YL should have good affinity for related targets and obvious effects (both up- and downregulating). Thus, a series of experiments, including cytobiology, animal-based pharmacodynamics, computer-assisted drug design, conventional content determination and pharmacokinetics, would be helpful for the selection and final confirmation of Q-markers. METHODS: The capsule was first administered to Wistar mice fed a high-fat diet and tested for their triglycerides (TG) and total cholesterol (TC) values to evaluate the effectiveness of YL. Then, liver tissue was extracted for gene expression. According to the results, the compounds in YL with good affiliation were selected and determined using UHPLC-MS-MS, and those with adequate results in the capsule were chosen as Q-marker candidates. Finally, pharmacokinetics research was performed; the candidates with desirable metabolite and bioavailability parameters were confirmed as Q-markers of YL. RESULTS: YL capsule was capable of lowering TG and TC levels. For target selection, the expression of LXR mRNA increased significantly at all three tested dosages. Downstream genes, such as LCAT, CYP7A1, and ABCA1, and intestinal FXR mRNA also showed significant increases in expression. For screening of the Q-marker candidates, 5 compounds were selected according to abovementioned results. The pharmacokinetics research demonstrated that the rats exploited lupeol and ginsenoside Rb3 in a desirable pattern with adequate bioavailability, which confirmed their roles as lipid regulatory Q-markers. CONCLUSION: The YL capsule was demonstrated to have obvious lipid regulatory effects, which are mainly exerted by targeting LXR and its related pathway. Lupeol and ginsenoside Rb3 were validated as Q-markers that represent the anti-hyperlipidemia activity of the capsule.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Receptores X do Fígado/metabolismo , Animais , Biomarcadores/análise , Cápsulas , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Medicamentos de Ervas Chinesas/análise , Regulação da Expressão Gênica/efeitos dos fármacos , Ginsenosídeos/farmacocinética , Hiperlipidemias/etiologia , Hipolipemiantes/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado/genética , Camundongos , Triterpenos Pentacíclicos/farmacocinética , Controle de Qualidade , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Triglicerídeos/sangue
12.
Phytomedicine ; 59: 152775, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31005812

RESUMO

BACKGROUND: Ginsenosides were considered as the main bioactive constituents in Ginseng Radix et Rhizoma (GRR). However, because of high polarity, ginsenosides were hard to be absorbed in human or animal gastrointestinal tract after oral administration. Up to now, very few studies have been performed in the area of simultaneous pharmacokinetic analysis of multiple ginsenosides with similar structures. PURPOSE: This research aimed to compare the different absorption characteristics of ginsenosides and aglycones between GRR and Baoyuan decoction (BYD), one of formulas containing GRR, with the same dosage. METHODS: GRR and BYD extracts were prepared with same method. A single dose of GRR and BYD extracts were administrated to rats through gavage, respectively. A solid phase extraction method was used to purify the plasma samples. An ultra-fast liquid chromatography coupled with tandem mass spectrometry (UFLC-MS/MS) method was established and fully validated for quantitative analysis. In addition, an in vitro incubation of GRR extract with intestinal flora was conducted to confirm the influence of gut microbiota to the absorption of ginsenosides and aglycones. RESULTS: The results of incubation experiments showed that most high polar ginsenosides could transform to less polar ginsenosides via intestinal flora. The validated UFLC-MS/MS method was sensitive and precise to simultaneously analyze the pharmacokinetics of multiple ginsenosides. After oral administration of GRR and BYD extracts, the pharmacokinetic results showed that a total of 11 ginsenosides and 2 aglycones could be quantitatively determined in both groups of plasma. Besides, five compounds were only quantified in BYD extract group. In addition, another 21 ginsenosides could be qualitatively measured. CONCLUSION: The results indicated significant pharmacokinetic differences of ginsenosides and aglycones between two groups. For most less polar ginsenosides who had better bioactivity, the preparation was possessed of higher plasma concentrations. The comparative results indicated that some co-existing compounds in BYD might inhibit the exocytosis of ginsenosides. Moreover, what is worth mentioning, some ginsenosides and aglycones could only be detected and quantified a few hours later after administration to rats. Combining with the in vitro incubation experiments, the results demonstrated that transformation of ginsenosides in gastrointestinal tract via intestinal flora existed during absorption.


Assuntos
Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Ginsenosídeos/farmacocinética , Panax/química , Espectrometria de Massas em Tandem/métodos , Animais , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/química , Microbioma Gastrointestinal/efeitos dos fármacos , Ginsenosídeos/análise , Ginsenosídeos/química , Limite de Detecção , Masculino , Ratos Endogâmicos , Reprodutibilidade dos Testes , Rizoma/química , Sensibilidade e Especificidade
13.
Biomed Chromatogr ; 33(7): e4521, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30818413

RESUMO

Lizhong decoction (LZD), a classic formula, has been used to treat ulcerative colitis (UC) for thousands of years in clinical practice. However, the pharmacokinetic characteristics of its major bioactive components in rats under different physiological and pathological states are not clear. Thus, in this study, a rapid and sensitive analytical method, ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS) method, was developed and applied to simultaneously determine glycyrrhizic acid, liquiritin, isoliquiritin, glycyrrhizin, isoliquiritigenin, 6-gingerol, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Re in normal and UC rats after oral administration of LZD extract. A Waters BEH C18 UPLC column was used for chromatographic separation, while acetonitrile and 0.1% formic acid were selected as mobile phase. The linearity of nine analytes was >0.9920. Inter- and intra-day accuracy was ≤ 11.4% and precision was from 1.1 to 12.7%. Additionally, stable and suitable extraction recoveries were also obtained. The established method was validated and found to be specific, accurate and precise for nine analytes. Furthermore, it was successfully applied to the pharmacokinetic investigation of nine major components after oral administration of LZD extracts to normal and model rats, respectively. The results showed that the pharmacokinetic parameters (Cmax , Tmax , AUC0-t , AUC0-∞ ) in the plasma of UC rats were significantly different from those of normal rats, which could provide a reference for the clinical application of LZD.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Colite Ulcerativa/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Chalcona/análogos & derivados , Chalcona/sangue , Chalcona/química , Chalcona/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Ginsenosídeos/sangue , Ginsenosídeos/química , Ginsenosídeos/farmacocinética , Glucosídeos/sangue , Glucosídeos/química , Glucosídeos/farmacocinética , Ácido Glicirrízico/sangue , Ácido Glicirrízico/química , Ácido Glicirrízico/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
14.
J Pharm Biomed Anal ; 169: 254-259, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30878903

RESUMO

As one of the main constituents of Compound Danshen Dripping Pills (CDDP), Panax notoginseng (PN) plays a pivotal role in the treatment of cardiovascular diseases. Numerous researches have proved that the dammarane type saponins including notoginsenoside R1 (NR1), ginsenoside Rg1 (GRg1) and ginsenoside Rb1 (GRb1) are the main bioactive components of PN in CDDP. An efficient, realiable and sensitive liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis method for simultaneously detecting NR1, GRg1 and GRb1 in human plasma was established and applied to the pharmacokinetics study of the three PN saponins after oral administration of CDDP. The human plasma samples were processed using acetonitrile and the target materials were separated on an Eclipse plus C18 column (100 × 4.6 mm, 3.5 µm) with a gradient mobile phase consisted of water (containing 0.1% formic acid) and methanol. Within the concentration ranges of 0.25-50 ng/mL, each calibration curve exhibited an excellent linear relationship (r>0.998). The precision deviations of intra-day and inter-day analysis were lower than 9.0%, and accuracy error (RE%) ranged between 1.5% and 10.5%. The average recoveries of analytes were >64.0%. The established method was successfully applied to determine the pharmacokinetics of the three saponins in human plasma. In addition to providing guidance for clinical safe medication, the experimental results also provided a valuable and reliable basis for further pharmacological studies of PN in the human body after oral administration of CDDP.


Assuntos
Medicamentos de Ervas Chinesas/química , Plasma/química , Saponinas/sangue , Saponinas/farmacocinética , Administração Oral , Adulto , Cromatografia Líquida/métodos , Ginsenosídeos/sangue , Ginsenosídeos/química , Ginsenosídeos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Panax notoginseng/química , Saponinas/química , Espectrometria de Massas em Tandem/métodos , Triterpenos/sangue , Triterpenos/química , Triterpenos/farmacocinética , Adulto Jovem
15.
Biomed Microdevices ; 21(1): 18, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30783757

RESUMO

Colorectal cancer (CRC) is a major malignancy characterized by a high metastasis rate. Systematic chemotherapy is important for patients with advanced CRC. However, many limitations (e.g., side effects to normal organs, shorter circulation time, and unsatisfactory tumor inhibition results) of traditional chemotherapy restrict its further application. Thus, it is necessary to find a method to overcome these challenges and improve the efficacy of CRC treatment. In this study, 20(S)-ginsenoside (Rg3) co-loaded poly(ethylene glycol)-block-poly(L-glutamic acid-co-L-phenylalanine) (mPEG-b-P(Glu-co-Phe)) nanoparticles (Rg3-NPs) were prepared. mPEG-b-P(Glu-co-Phe)-based drug delivery systems are pH sensitive that can target cancer cells and circulate for longer in blood. Rg3 could be released rapidly from the nanoparticles within tumor cells. A subcutaneous colon cancer mouse model was developed to evaluate the anticancer efficiency of the Rg3-NPs. The in vivo study indicated that the Rg3-NPs could significantly inhibit tumor proliferation by decreasing the expressions of proliferating cell nuclear antigen, resulting in tumor apoptosis through the increased expressions of caspase-3. Our study demonstrated the marked potential of the Rg3-NPs to treat CRC.


Assuntos
Neoplasias do Colo , Sistemas de Liberação de Medicamentos/métodos , Ginsenosídeos , Nanopartículas , Animais , Linhagem Celular Tumoral , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Ginsenosídeos/química , Ginsenosídeos/farmacocinética , Ginsenosídeos/farmacologia , Humanos , Masculino , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Peptídeos/química , Peptídeos/farmacocinética , Peptídeos/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia , Ácido Poliglutâmico/química , Ácido Poliglutâmico/farmacocinética , Ácido Poliglutâmico/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Sep Sci ; 42(9): 1740-1749, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30805999

RESUMO

Notoginsenoside Fc, which is a protopanaxdiol-type saponin isolated from the leaves of Panax notoginseng, exhibits an exceptional antiplatelet aggregatory effect. To study the modulating effect of gastrointestinal contents on the metabolic profile and pharmacokinetics, pseudo germ-free rats were used to study the influence of the bacterial community structure on the metabolic profile. Glycosidase activities were measured using the spectrophotometric method. Biotransformations of notoginsenoside Fc in normal and pseudo germ-free rat intestinal microflora were systematically investigated using ultra high performance liquid chromatography with tandem quadrupole/time-of-flight mass spectrometry. Moreover, a liquid chromatography with tandem mass spectrometry method was established for simultaneous determination of the notoginsenoside Fc prototype and its degradation products. Through an in vivo pharmacokinetic study, the pharmacokinetic characteristics were compared between normal rats and pseudo germ-free rats. During the in vitro biotransformation, seven deglycosylated products were detected and identified after incubation in the intestinal bacteria of normal rats. In pseudo germ-free rats, glycosidase activities were significantly decreased, and no obvious degradation occurred. In an in vivo study, the systemic exposure was significantly increased 40%, as evidenced by the area under the blood concentration-time curve from time zero to infinity value and half-life value, which were prolonged more in the pseudo germ-free group than in normal rats. The results demonstrate that patients who use intestinal bacteria-metabolized herbs, such as panax notoginseng, should understand the profile of intestinal bacteria to ensure therapeutic efficacy.


Assuntos
Bactérias/metabolismo , Medicamentos de Ervas Chinesas/química , Microbioma Gastrointestinal , Ginsenosídeos/química , Panax notoginseng/química , Animais , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Ginsenosídeos/metabolismo , Ginsenosídeos/farmacocinética , Intestinos/microbiologia , Masculino , Metaboloma , Folhas de Planta/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem
17.
J Pharm Biomed Anal ; 166: 52-65, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30609394

RESUMO

Danqi Tongmai tablet (DQTT), an innovative TCM formula under clinical trials, is composed of salvianolic acids (SA) and panax notoginsenosides (PNE) for the treatment of coronary heart disease and angina pectoris. However, the in vivo herb-herb interaction of DQTT remains unclear. In the present research, a rapid, reliable and sensitive method for quantitative analysis of multi-notoginsenoside in rat plasma based on ultra high performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-TQ/MS) was established and then applied to explore the herb-herb interaction mechanism of DQTT based on the pharmacokinetics in acute myocardial ischemia (AMI) and sham rats after oral administration of DQTT and PNE. Compared with sham rats after oral administration of PNE, the values of AUC0-t for Rf and Rb2 were significantly higher in DQTT group. Compared with AMI rats after oral PNE, AUC0-t for NR1, Rg1, Re, Rb1, Rd, Rg2, Rb2, NR2, Rh1, F1 and F2 were significantly increased after oral administration of DQTT. These results hinted that SA could improve the bioavailability of notoginsenosides in AMI rats, which provides scientific information for better understanding the herb-herb interaction mechanism and offers a reference for clinical administration of DQTT. Additionally, the presently developed methodology was simple, robust, accurate, precise, and would be useful for the pharmacokinetic studies for all kinds of notoginsenosides and other herbal saponins.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Ginsenosídeos/farmacocinética , Interações Ervas-Drogas , Panax/metabolismo , Animais , Disponibilidade Biológica , Ginsenosídeos/sangue , Masculino , Isquemia Miocárdica/sangue , Ratos , Comprimidos
18.
Acta Pharmacol Sin ; 40(6): 833-849, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30327544

RESUMO

ShenMai, an intravenous injection prepared from steamed Panax ginseng roots (Hongshen) and Ophiopogon japonicus roots (Maidong), is used as an add-on therapy for coronary artery disease and cancer; saponins are its bioactive constituents. Since many saponins inhibit human organic anion-transporting polypeptides (OATP)1B, this investigation determined the inhibition potencies of circulating ShenMai saponins on the transporters and the joint potential of these compounds for ShenMai-drug interaction. Circulating saponins and their pharmacokinetics were characterized in rats receiving a 30-min infusion of ShenMai at 10 mL/kg. Inhibition of human OATP1B1/1B3 and rat Oatp1b2 by the individual saponins was investigated in vitro; the compounds' joint inhibition was also assessed in vitro and the data was processed using the Chou-Talalay method. Plasma protein binding was assessed by equilibrium dialysis. Altogether, 49 saponins in ShenMai were characterized and graded into: 10-100 µmol/day (compound doses from ShenMai; 7 compounds), 1-10 µmol/day (17 compounds), and <1 µmol/day (25 compounds, including Maidong ophiopogonins). After dosing, circulating saponins were protopanaxadiol-type ginsenosides Rb1, Rb2, Rc, Rd, Ra1, Rg3, Ra2, and Ra3, protopanaxatriol-type ginsenosides Rg1, Re, Rg2, and Rf, and ginsenoside Ro. The protopanaxadiol-type ginsenosides exhibited maximum plasma concentrations of 2.1-46.6 µmol/L, plasma unbound fractions of 0.4-1.0% and terminal half-lives of 15.6-28.5 h (ginsenoside Rg3, 1.9 h), while the other ginsenosides exhibited 0.1-7.7 µmol/L, 20.8-99.2%, and 0.2-0.5 h, respectively. The protopanaxadiol-type ginsenosides, ginsenosides without any sugar attachment at C-20 (except ginsenoside Rf), and ginsenoside Ro inhibited OATP1B3 more potently (IC50, 0.2-3.5 µmol/L) than the other ginsenosides (≥22.6 µmol/L). Inhibition of OATP1B1 by ginsenosides was less potent than OATP1B3 inhibition. Ginsenosides Rb1, Rb2, Rc, Rd, Ro, Ra1, Re, and Rg2 likely contribute the major part of OATP1B3-mediated ShenMai-drug interaction potential, in an additive and time-related manner.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Ginsenosídeos/farmacocinética , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Administração Intravenosa , Animais , Combinação de Medicamentos , Interações de Medicamentos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/metabolismo , Ginsenosídeos/administração & dosagem , Ginsenosídeos/sangue , Ginsenosídeos/metabolismo , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Ophiopogon/química , Panax/química , Ligação Proteica , Ratos Sprague-Dawley , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo
19.
Biomed Pharmacother ; 110: 95-104, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30466007

RESUMO

Ginseng is often prescribed together with cisplatin for treatment of cancer, but the interaction between ginseng and cisplatin is still unknown. This study employed ginsenoside Rb1 (Rb1), one of the major components in ginseng, to explore the effects and involved mechanisms of cisplatin on the pharmacokinetics of ginseng. The effects of cisplatin on the pharmacokinetics of Rb1 and its bioactive metabolites Rd, Rg3, and F2 were investigated by using A549-bearing mice with and without cisplatin intervention. Our data showed that cisplatin could significantly decrease the AUC(0-t) and Cmax of Rd, Rg3, and F2, except Rb1. To evaluate the involved mechanisms, feces and intestinal mucosa were collected to explore the effects of cisplatin on the gut metabolism of Rb1 in vitro; meanwhile, Caco-2 cell model and small intestine histological characters were examined to evaluate the effects of cisplatin on the gut absorptive areas and permeability. The mechanisms involved may be mainly related to the comprehensive contributions of inhibited intestinal bacteria and mucosa metabolisms, narrowed intestinal absorptive area, increased efflux ratio of intestinal absorption and enhanced intestinal permeability. All these findings suggested that the dosage of ginseng traditionally used for health protection should be adjusted when it was prescribed together with cisplatin in the treatment of cancer.


Assuntos
Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Ginsenosídeos/farmacocinética , Interações Ervas-Drogas/fisiologia , Absorção Intestinal/fisiologia , Ensaios Antitumorais Modelo de Xenoenxerto , Células A549 , Animais , Células CACO-2 , Humanos , Absorção Intestinal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Distribuição Aleatória , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
20.
J Med Food ; 22(3): 257-263, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30543483

RESUMO

Compound K (CK) is a metabolite of a saponin in Panax ginseng, formed from ginsenoside, a triterpenoid glycoside, by human intestinal bacteria. Lactobacillus paracasei A221 isolated from fermented food can hydrolyze (deglycosylate) the main ginsenoside, ginsenoside Rb1, and generate CK. However, the pharmacokinetics of L. paracasei A221 fermented ginseng (FG) and nonfermented ginseng (NFG) have not been investigated so far. The aim of this study was to investigate the pharmacokinetics of CK after oral administration of single doses of FG and NFG in healthy Japanese adults. An open-label, randomized, single-dose, two-period, crossover study was conducted in 12 Japanese healthy volunteers (five men and seven women, aged 40-60 years). All subjects were equally allocated into two groups and administered tablets containing FG or NFG. Until 24 h after the administration, blood samples were sequentially collected, plasma concentrations of CK were measured, and the pharmacokinetic parameters were calculated. We also expected restoration of decreased testosterone level as one of the beneficial effects of FG and measured plasma total testosterone concentrations in male volunteers. The means of Tmax, Cmax, and area under the concentration-time curve (AUC) were significantly different between the two groups. In the FG group, AUC0-12h (ng h/mL) and AUC0-24h (ng h/mL) were, respectively, 58.3- and 17.5-fold higher than those in the NFG group. Moreover, mean testosterone concentration in the FG group significantly increased 24 h after administration. These results showed that the main ginsenoside metabolite of ginseng, CK, produced by L. paracasei A221 has potential utility in health maintenance in healthy middle-aged and old Japanese adults.


Assuntos
Ginsenosídeos/farmacocinética , Lactobacillus paracasei/metabolismo , Panax/microbiologia , Adulto , Estudos Cross-Over , Feminino , Fermentação , Ginsenosídeos/administração & dosagem , Ginsenosídeos/sangue , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Panax/química , Testosterona/sangue
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