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1.
Biomed Chromatogr ; 34(1): e4701, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31596954

RESUMO

Patrinia villosa (Thunb.) Juss. (PVJ) is described as pungent, bitter and slightly cold in Chinese medicine, and is associated with the large intestine, stomach and liver meridians. The preliminary experiments of our research team proved that PVJ total flavonoids have excellent inhibitory effects on liver cancer cells. The present experiment uses the UPLC-Q-TOF-MS technology and serum pharmacochemistry methods to analyze the chemical components in vitro and in vivo of PVJ antiliver tumors. A total of 14 chemical components were identified in the total flavonoids extract of PVJ, and it is mainly composed of flavonoids, flavonones, flavonols and phenolic acids. At the same time, seven prototypical components and seven metabolic components were detected in the drug-containing plasma. Hydrocaffeate and scutellarein are the phase I metabolites of caffeic acid and scutellarin, respectively. Sulfated apigenin, sulfated luteolin, sulfated kaempferol and methylated kaempferol are the II phase metabolites of apigenin, luteolin, kaempferol, respectively. The experiment provides a reference for the research and development of antitumor drug candidates, and provides a basis for revealing the bioactive components of PVJ and the antitumor mechanism.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Flavonoides/sangue , Patrinia/química , Extratos Vegetais/sangue , Animais , Flavonoides/química , Masculino , Espectrometria de Massas , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley
2.
J Pharm Biomed Anal ; 177: 112836, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31473481

RESUMO

Xian-Ling-Gu-Bao capsule (XLGB) is an effective traditional Chinese medicine prescription (TCMP) that is used for the prevention and treatment of osteoporosis in China. A rapid, simple, efficient and stable method based on UPLC-MS/MS technology was developed for simultaneous determination of multiple components of XLGB in rat plasma. Mass spectrometric detection was performed in multiple reaction monitoring (MRM) mode with electrospray ionization (ESI). For twenty-one selected quantitative prototypes, all calibration curves showed favourable linearity (r>0.9932) in linear ranges. The lower limits of quantification (LLOQs) were 2 ng/mL for psoralen (PL), 2.5 ng/mL for asperosaponin VI (AS), 1 ng/mL for isopsoralen (IPS) and sweroside (SW), 0.5 ng/mL for magnoflorine (MA), bavachinin (BVN), tanshinone IIA (TA), timosaponin BII (TBII) and icaritin (ICT), 0.1 ng/mL for epimedin B (EB) and epimedin C (EC), 0.05 ng/mL for icariin (IC), isobavachalcone (IBC), psoralidin (PD), bavachin (BV), bavachalcone (BC), epimedin A (EA) and isobavachin (IBV), 0.02 ng/mL for neobavaisoflavone (NEO) and icariside I (ICI) and 0.01 ng/mL for icariside II (ICII). The intra-day and inter-day (low, medium, high) precision (relative standard deviation) for all analytes was less than 8.63%, and the accuracies (as relative error) were in the range of -12.45% to 8.91%. Extraction recoveries and matrix effects of analytes and IS were acceptable. All analytes were stable during the assay and storage in plasma samples. The validated method was successfully applied to the pharmacokinetics (PK) studies of the twenty-one prototypes at pharmacodynamic doses (0.3 and 1 g/kg/day). In addition, dynamic profiles of 28 metabolites (phase II conjugates: 23 glucuronide conjugates, 2 sulfate conjugates and 3 glucuronide or sulfate conjugates) were also monitored by their area/IS area-time curves. As a result, coumarins, prenylated flavonoids from Psoraleae Fructus, alkaloids and prenylated flavonol glycosides from Epimedii Herba, and iridoid glycosides, triterpenoid saponins from Dipsaci Asperoidis Radix were considered to be the key effective substances of XLGB due to their high exposure and appropriate pharmacokinetic features. This is the first report to reveal pharmacodynamic ingredients by a reversed pharmacodynamic (PD) - pharmacokinetics (PK) study.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Aporfinas/administração & dosagem , Aporfinas/sangue , Aporfinas/farmacocinética , Cápsulas , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/análise , Feminino , Ficusina/administração & dosagem , Ficusina/sangue , Ficusina/farmacocinética , Flavonoides/administração & dosagem , Flavonoides/sangue , Flavonoides/farmacocinética , Furocumarinas/administração & dosagem , Furocumarinas/sangue , Furocumarinas/farmacocinética , Glucosídeos Iridoides/administração & dosagem , Glucosídeos Iridoides/sangue , Glucosídeos Iridoides/farmacocinética , Modelos Animais , Ratos , Saponinas/administração & dosagem , Saponinas/sangue , Saponinas/farmacocinética
3.
J Pharm Biomed Anal ; 177: 112869, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31539714

RESUMO

A rapid, sensitive, selective, and accurate UPLC-MS/MS method was developed and fully validated for the simultaneous determination of quercitrin, phloridzin, quercetin, and phloretin in rat plasma after oral administration of Malus hupehensis (Pamp.) Rehd extracts. The pharmacokinetic parameters of oral phloridzin monomer and phloridzin in the extract were also compared. Plasma samples were processed with a simple protein precipitation technique using methanol, followed by chromatographic separation using a Sun Fire ™C18 column. Bergenin was used an internal standard (IS). A 15.0 min linear gradient elution was used at a flow rate of 0.8 mL/min with a mobile phase of 0.1% formic acid in water and acetonitrile. The analytes and IS were detected using negative ion electrospray ionization in multiple reaction monitoring mode. The developed method exhibited good linearity (r ≥ 0.9911), and the lower limits of quantification ranged from 0.2 to 0.8 ng/mL for the four analytes. Intra-day and inter-day precision were both less than 8.5% and were within the acceptable limits. Matrix effect and recovery efficiency of all analytes were found to be >76.2% and >71.4%, respectively. Stability results showed that the analytes were stable at all conditions. Additionally, the carry-over effect and dilution effect were within the acceptance range. The developed method was successfully applied to a pharmacokinetic study of four analytes in rats after oral administration of Malus hupehensis (Pamp.) Rehd. extracts.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Flavonoides/farmacocinética , Malus/química , Chás de Ervas , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/análise , Flavonoides/administração & dosagem , Flavonoides/sangue , Masculino , Modelos Animais , Folhas de Planta/química , Ratos , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
4.
Eklem Hastalik Cerrahisi ; 30(3): 282-8, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31650926

RESUMO

OBJECTIVES: This study aims to evaluate the effects of locally applied icariin on bone fracture healing in femur fractured rat model. MATERIALS AND METHODS: The study included 64 male Sprague-Dawley rats (mean age 6 months; weighing, 280-490 g) in eight main study groups. Fracture healing process and level were evaluated with radiography, histopathology and dual energy X-ray absorptiometry to investigate the effects of local administration of icariin at varying doses, which is an exogenous osteo-inductive substance. Activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured in the peripheral blood in addition to glutathione (GSH) and myeloperoxidase (MPO) levels to investigate the effects of icariin on the oxidant-antioxidant systems. RESULTS: Radiological bone mineral density measurements and histopathological findings revealed that icariin improved all these parameters in the two healing periods tested. Superoxide dismutase activity decreased in association with local icariin application to the fractured side whereas GPx and GSH increased and MPO remained unchanged. Icariin increased the GPx and GSH levels which are responsible from scavenging hydroxyl radical and hydrogen peroxide. CONCLUSION: Locally administered icariin to the fracture accelerated bone healing by reducing the oxidative stress.


Assuntos
Densidade Óssea/efeitos dos fármacos , Flavonoides/farmacologia , Consolidação da Fratura/efeitos dos fármacos , Depuradores de Radicais Livres/farmacologia , Absorciometria de Fóton , Animais , Relação Dose-Resposta a Droga , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Fêmur/cirurgia , Flavonoides/administração & dosagem , Flavonoides/sangue , Depuradores de Radicais Livres/administração & dosagem , Depuradores de Radicais Livres/sangue , Glutationa Peroxidase/sangue , Masculino , Modelos Animais , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/sangue
5.
J Agric Food Chem ; 67(43): 11955-11968, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31595748

RESUMO

Increased processing of pulses generates large volumes of hulls, which are known as an excellent source of phenolic antioxidants. However, the bioavailability and in vivo activity of these phenolics are rarely reported. This research was therefore carried out to study the absorption, metabolism, and in vivo antioxidant activities of green pea hull (GPH) phenolics using ultrahigh-pressure liquid chromatography with a linear ion trap-high-resolution Orbitrap mass spectrometry and an oxidative stress rat model. A total of 31 phenolics, including 4 phenolic acids, 24 flavonoids, and 3 other phenolics, were tentatively identified. Ten of these phenolics and 49 metabolites were found in the plasma and urine of rats, which helped to explain the favorable changes by GPH phenolics in key antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and glutathione) and indicators (total antioxidant capacity, malondialdehyde) in the plasma and different tissues of rats. This is the first comprehensive report on dry pea hull phenolics and their bioavailability, metabolic profiles, and mechanisms of in vivo antioxidant activities.


Assuntos
Antioxidantes/metabolismo , Ervilhas/metabolismo , Fenóis/sangue , Fenóis/urina , Extratos Vegetais/sangue , Extratos Vegetais/urina , Resíduos/análise , Animais , Antioxidantes/química , Disponibilidade Biológica , Feminino , Flavonoides/sangue , Flavonoides/metabolismo , Flavonoides/urina , Hidroxibenzoatos/sangue , Hidroxibenzoatos/metabolismo , Hidroxibenzoatos/urina , Estrutura Molecular , Ervilhas/química , Fenóis/química , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley
6.
J Vet Pharmacol Ther ; 42(5): 580-584, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31373697

RESUMO

The purpose of this study was to determine the pharmacokinetics of baicalin after intravenous and intramuscular administration of sodium baicalin at 50 mg/kg to piglets. Plasma baicalin levels were determined by high-performance liquid chromatography. The plasma concentration-time data of baicalin for both administration routes were best described by two-compartmental open model. The area under the plasma concentration-time curve and the elimination half-lives were 77.47 ± 6.14 µg/ml × h and 1.73 ± 0.16 hr for intravenous and 64.85 ± 5.67 µg/ml × h and 2.42 ± 0.15 hr for intramuscular administration, respectively. The apparent volume of distribution and body clearance were 1.63 ± 0.23 L/kg and 2.74 ± 0.30 L h-1  kg-1 for intravenous and 0.51 ± 0.10 L/kg and 0.78 ± 0.08 L h-1  kg-1 for intramuscular routes, respectively. An intramuscular injection of sodium baicalin in piglets resulted in rapid and complete absorption, with a mean maximal plasma concentration of 77.28 ± 7.40 µg/ml at 0.17 hr and a high absolute bioavailability of 83.73 ± 5.53%.


Assuntos
Anti-Infecciosos/farmacocinética , Flavonoides/farmacocinética , Suínos/sangue , Animais , Anti-Infecciosos/administração & dosagem , Anti-Infecciosos/sangue , Área Sob a Curva , Flavonoides/administração & dosagem , Flavonoides/sangue , Meia-Vida , Injeções Intramusculares , Injeções Intravenosas
7.
Biomed Chromatogr ; 33(12): e4680, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31415097

RESUMO

In this study, an accurate and reliable method of ultra-performance liquid chromatography coupled with a triple-quadrupole tandem mass spectrometry was firstly developed and fully validated for the simultaneous determination of epicatechin, neoastilbin, astilbin, isoastilbin, engeletin and resveratrol in rat plasma after administration of Smilacis glabrae Roxb. extract. Naringenin was used as an internal standard (IS). The analyte and IS were separated on a C18 column by gradient elution with a mobile phase of acetonitrile-0.3% acetic acid at a flow rate of 0.25 mL/min for a total run time of 8 min. The method was validated in terms of selectivity, linearity, precision, accuracy, extraction recovery, matrix effect and stability. The developed method was successfully applied to determine the main pharmacokinetic parameters of six components in rat plasma.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/análise , Medicamentos de Ervas Chinesas/farmacocinética , Flavonoides/sangue , Flavonoides/química , Flavonoides/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Resveratrol/sangue , Resveratrol/química , Resveratrol/farmacocinética
8.
J Chromatogr A ; 1603: 44-50, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31272729

RESUMO

This paper proposed a double salting-out effect assisted heat-shrinkable tubing liquid phase microextraction (LPME). In the study, a low price and handy heat-shrinkable tubing was used as carrier of extraction solvent and salt film, which was placed in sample solution containing certain concentration of salt for concentrating and enriching flavonoids from human plasma. Through the double salting-out effect in different regions, this microextraction method has a good present to enhance the extraction efficiency and enrichment factors of the target analytes. Several key parameters affecting the extraction efficiency were investigated, including the type of extraction solvent, the occurring region of salting-out effect, salt concentration, pH of sample phase, stirring rate, extraction time, and volume of sample phase. Also, the mechanism of the procedure was described. Under the optimum conditions, excellent linearities with r≥ 0.9912 were obtained, the limits of detection were 2.5-150 ng/mL, the average recoveries ranged from 90.3% to 111.2%. In the new procedure, the low-cost and stable heat-shrinkable tubing was first used as carrier in LPME, combined with high performance liquid chromatography (HPLC), has been successfully applied for the determination of the trace-level target analytes in human plasma.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Flavonoides/sangue , Flavonoides/isolamento & purificação , Microextração em Fase Líquida/métodos , Cloreto de Sódio/química , Temperatura Alta , Humanos
9.
Biomed Chromatogr ; 33(11): e4632, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31264241

RESUMO

Cirsium setosum (Willd.) MB. has been reported to exert significant anti-hemorrhagic, anti-inflammation, antimicrobial, sedative and detoxicating efficacy. It has been widely used to treat gastrointestinal bleeding, uterine bleeding, infectious hepatitis and cardiovascular disease in China. Recent studies have shown that flavonoids are the main active components in C. setosum. Nevertheless, to the best of our knowledge, there is no report concerning the simultaneous determinations and pharmacokinetics of constituents in C. setosum flavonoids in rat plasma. In this study, a rapid, sensitive and selective triple quadrupole liquid chromatography-mass spectrometry method was developed to determine eight analytes from the flavonoids of C. setosum in rat plasma. In addition, the pharmacokinetic study of the eight analytes in rats after oral administration of C. setosum flavonoids was successfully completed through this method. According to the pharmacokinetic parameters of the eight analytes, rutin, naringin, quercetin, acacetin, wogonin were the long-acting components of the C. setosum flavonoids, with long elimination time and high bioavailability. Of note, the method developed in this study fills a blank in pharmacokinetic studies of C. setosum flavonoids. Our findings provide valuable views on the understanding of the absorption mechanism of C. setosum flavonoids and their clinical efficacy.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Cirsium , Medicamentos de Ervas Chinesas/farmacocinética , Flavonoides/sangue , Espectrometria de Massas/métodos , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes
10.
Molecules ; 24(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340434

RESUMO

Eupatorin is the major bioactive component of Java tea (Orthosiphon stamineus), exhibiting strong anticancer and anti-inflammatory activities. However, no research on the metabolism of eupatorin has been reported to date. In the present study, ultra-high-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) combined with an efficient online data acquisition and a multiple data processing method were developed for metabolite identification in vivo (rat plasma, bile, urine and feces) and in vitro (rat liver microsomes and intestinal flora). A total of 51 metabolites in vivo, 60 metabolites in vitro were structurally characterized. The loss of CH2, CH2O, O, CO, oxidation, methylation, glucuronidation, sulfate conjugation, N-acetylation, hydrogenation, ketone formation, glycine conjugation, glutamine conjugation and glucose conjugation were the main metabolic pathways of eupatorin. This was the first identification of metabolites of eupatorin in vivo and in vitro and it will provide reference and valuable evidence for further development of new pharmaceuticals and pharmacological mechanisms.


Assuntos
Flavonoides/farmacocinética , Glicoconjugados/isolamento & purificação , Microssomos Hepáticos/metabolismo , Orthosiphon/química , Acetilação , Animais , Bile/química , Biotransformação , Fezes/química , Flavonoides/sangue , Flavonoides/urina , Microbioma Gastrointestinal/fisiologia , Glicoconjugados/metabolismo , Hidrogenação , Masculino , Metilação , Oxirredução , Extratos Vegetais/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
11.
Artigo em Inglês | MEDLINE | ID: mdl-31177049

RESUMO

Diosmin (diosmetin-7-O-rutinoside) and its aglycone diosmetin, natural bioflavonoids distributing in a variety of citrus fruits and Chinese herbal medicines, possessed positive effects against hepatic, renal, lung, gastric, cerebral and cardiac injury. However, the in vivo metabolic profiles of diosmin and diosmetin in urine, plasma and feces still remain ambiguous. In this study, metabolites of diosmin and diosmetin were identified using an UHPLC-LTQ-Orbitrap MSn strategy coupled with multiple metabolite templates, extracted ion chromatograms (EICs) and diagnostic product ions (DPIs). As a result, 46 diosmetin metabolites and 64 diosmin metabolites were respectively identified in rat biological samples. Methylation, demethylation, hydroxylation, glycosylation, glucuronidation, diglucuronidation and sulfation were common metabolic pathways of diosmetin and diosmin, while demethoxylation, decarbonylation, dihydroxylation and dehydroxylation were particular metabolic pathways of diosmin comparing with that of diosmetin. Diosmetin was not detected in all the biological samples, suggesting that it was quickly transformed into other metabolites in vivo. Diosmin and diosmetin-7-O-glucoside identified in urine and feces as well as their subsequent metabolites accounted for a substantial part of all the diosmin metabolic products. Metabolic profiles of diosmetin and diosmin indicated that they were primarily excreted through the urine route possibly originating from the dominant role of their phase II metabolism in vivo. Our results have provided a better understanding of the similarities and differences in pharmacodynamics and pharmacokinetics of diosmetin and diosmin in the future.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Diosmina/sangue , Diosmina/urina , Fezes/química , Flavonoides/sangue , Flavonoides/urina , Espectrometria de Massas/métodos , Animais , Masculino , Plasma/química , Ratos , Ratos Sprague-Dawley
12.
J Agric Food Chem ; 67(23): 6665-6671, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31117500

RESUMO

A new sample processing method for analyzing flavonol metabolites in plasma using enzymatic proteolysis was developed and validated. Four endopeptidases were examined regarding their influence on the analyte recovery of quercetin-3- O-glucuronide (Q3GlcA). Methanol was added to inactivate and precipitate the enzymes, and samples were concentrated via evaporation prior to UHPLC-MS analysis. Quercetin-3- O-rutinoside (Q3Rut) was used as an internal standard. The selectivity and accuracy of the established UHPLC-ESI-MS n method showed a coefficient of variation (CV) of the repeatability of the measuring instrument of 1.7% for Q3GlcA. The average recovery of Q3GlcA was approximately 67% with an interday method precision of 24% and r = 46.9 as its repeatability. Therefore, enzymatic proteolysis has proven to be a suitable alternative to the methods previously described in the literature, such as solid-phase extraction (SPE). Still, the method has only been validated for Q3GlcA, but its applicability to other substance classes seems possible.


Assuntos
Coleta de Amostras Sanguíneas/métodos , Cromatografia Líquida de Alta Pressão/métodos , Plasma/química , Espectrometria de Massas em Tandem/métodos , Animais , Proteínas de Bactérias/química , Biocatálise , Flavonoides/sangue , Flavonoides/isolamento & purificação , Humanos , Peptídeo Hidrolases/química , Proteólise , Streptomyces griseus/enzimologia , Suínos
13.
Biomed Chromatogr ; 33(8): e4546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30937924

RESUMO

A sensitive and reliable LC-MS/MS method was developed and validated for simultaneous quantification of the major components of Huangqi-Honghua extact in rat plasma, including hydroxysafflor yellow A (HSYA), astragaloside IV (ASIV), calycosin-7-O-ß-d-glucoside (CAG), calycosin, calycosin-3'-O-glucuronide (C-3'-G) and calycosin-3'-O-sulfate (C-3'-S). After extraction by protein precipitation with acetonitrile and methanol from plasma, the analytes were separated on a Hypersil BDS C18 column by gradient elution with acetonitrile and 5 mM ammonium acetate. The detection was carried out on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization source switched between negative and positive modes. HSYA was monitored in negative ionization mode from 0 to 4.9 min, and ASIV, CAG, calycosin, C-3'-G and C-3'-S were determined in positive ionization mode from 4.9 to 10 min. The lower limits of quantification of the analytes were 6.25 ng/mL for HSYA, 0.781 ng/mL for CAG and 1.56 ng/mL for ASIV and calycosin. The intra- and inter-assay precision (RSD) values were within 13.43%, and accuracy (RE) ranged from -8.75 to 9.92%. The validated method was then applied to the pharmacokinetic study of HSYA, ASIV, CAG, calycosin, C-3'-G and C-3'-S in rat after an oral administration of Huangqi-Honghua extract.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Flavonoides/sangue , Saponinas/sangue , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Carthamus tinctorius , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Flavonoides/química , Flavonoides/farmacocinética , Glucuronídeos/sangue , Glucuronídeos/química , Glucuronídeos/farmacocinética , Limite de Detecção , Modelos Lineares , Masculino , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Saponinas/química , Saponinas/farmacocinética
14.
Biopharm Drug Dispos ; 40(3-4): 151-161, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30931529

RESUMO

GL-V9, a derivative of wogonin, has potent anti-cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL-V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL-V9, an in situ single-pass perfusion model and a Caco-2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (Fa × Fg ) was 21.28 ± 5.38%. The unmetabolized fraction in the gut wall (Fgut wall ) was 98.59 ± 9.74%, while the hepatic bioavailability (Fh ) was 29.11 ± 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL-V9. The effective permeability (Peff ) in the duodenum and jejunum was 1.34 ± 0.50 × 10-4 and 0.90 ± 0.27 × 10-4  cm/s, respectively. The high permeability of GL-V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Clint, CYP450s and UGT of GL-V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL-V9 possesses higher permeability than wogonin and the metabolism of GL-V9 is related to its disposition in rat intestine and liver.


Assuntos
Antineoplásicos/farmacocinética , Flavonoides/farmacocinética , Animais , Antineoplásicos/sangue , Antineoplásicos/química , Disponibilidade Biológica , Células CACO-2 , Flavonoides/sangue , Flavonoides/química , Suco Gástrico/química , Humanos , Absorção Intestinal , Mucosa Intestinal/metabolismo , Secreções Intestinais/química , Fígado/metabolismo , Masculino , Microssomos/metabolismo , Ratos Sprague-Dawley
15.
J Pharm Biomed Anal ; 171: 81-98, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30981193

RESUMO

Bu-Zhong-Yi-Qi-Tang (BZYQT), a famous traditional Chinese medicine prescription (TCMP), has been extensively used for conditioning sub-health status and diseases caused by spleen-qi deficiency in China for over 700 years. BZYQT is prevalent not only in China, but also in Japan and South Korea for the clinical treatment of chronic diseases, such as fatigue, tuberculosis and loss of appetite after surgery. However, due to a lack of research on the holistic metabolism of BZYQT, the in vivo bioactive components of BZYQT remain unclear, hindering further study of its in vivo mechanism of action and quality control. In the present study, a four-step integrated strategy based on ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry (UHPLC-Q-TOF/MS) was established to systematically screen the in vivo xenobiotics of BZYQT. Ultimately, a total of 162 xenobiotics (59 prototypes and 103 metabolites) were identified or tentatively characterized, including 48 in plasma, 147 in urine and 58 in feces, while the in vivo metabolic profile of atractylenolide III (a major component of BZYQT) was elucidated for the first time. The xenobiotics of BZYQT mainly included flavonoids from Astragali Radix, Glycyrrhizae Radix et Rhizoma and Citrus reticulatae Pericarpium; lactones from Angelicae Sinensis Radix and Atractylodis Macrocephalae Rhizoma; and triterpenoid saponins from Cimicifugae Rhizoma. After oral administration, BZYQT-related components underwent diverse metabolic pathways. Among them, flavonoids mainly underwent glucuronidation, sulfation and demethylation, while lactones mainly underwent hydroxylation and acetylcysteine conjugation, and deglycosylation was the major metabolic reaction of saponins. Our investigation gives a comprehensive analysis of the metabolic characteristics of BZYQT and will provide an important basis for further studying the pharmacokinetics of BZYQT to explore its in vivo disposal features and discover its in vivo bioactive components.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Flavonoides/análise , Espectrometria de Massas em Tandem/métodos , Triterpenos/análise , Administração Oral , Animais , Fezes/química , Flavonoides/sangue , Flavonoides/urina , Lactonas/metabolismo , Masculino , Desentoxicação Metabólica Fase I , Desintoxicação Metabólica Fase II , Metaboloma , Estrutura Molecular , Ratos Sprague-Dawley , Sesquiterpenos/metabolismo , Triterpenos/sangue , Triterpenos/urina
16.
J Pharm Biomed Anal ; 172: 103-112, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31029799

RESUMO

Chinese medicinal herbs danshen and huangqin have attracted attention in spinal cord injury (SCI) treatment. Purpose of this study was to investigate and compare the pharmacokinetic characteristics of 4 phenolic acids and 4 flavonoids in SCI rat plasma after orally administrate danshen, huangqin and combined extract of these two herbs (CDH). Thus, a rapid and sensitive ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for simultaneously quantitative determination of tanshinol, protocatechualdehyde, protocatechuic acid, salvianolic acid A, baicalein, baicalin, wogonin and wogonoside. After inducing a contusion injury by a weight-drop device, SCI rats were orally administrated a single dose (12.5 g/kg) of danshen, huangqin and CDH extracts, respectively. Then, blood samples at different time points were collected and analyzed. In CDH group, Cmax and AUC of tanshinol, protocatechualdehyde and protocatechuic acid significantly declined, while those of salvianolic acid A enhanced. These changes were beneficial for danshen to treat SCI. As for flavonoids, double peaks were observed in huangqin group, while this phenomenon disappeared in CDH group. Concomitantly, Cmax and AUC declined after administrated CDH. These alterations were due to influence of danshen active constituents on absorption and transportation process of flavonoids. Therefore, danshen and huangqin significantly influenced pharmacokinetic profile and parameters of each other, thus exert synergistic therapeutic effect in SCI treatment.


Assuntos
Medicamentos de Ervas Chinesas/farmacocinética , Salvia miltiorrhiza/química , Scutellaria baicalensis/química , Traumatismos da Medula Espinal/tratamento farmacológico , Administração Oral , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Combinação de Medicamentos , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Flavonoides/sangue , Humanos , Hidroxibenzoatos/sangue , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/sangue , Traumatismos da Medula Espinal/etiologia , Espectrometria de Massas em Tandem
17.
Biomed Chromatogr ; 33(7): e4524, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30821835

RESUMO

A sensitive and validated method of liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established to test the plasma concentrations of active ingredients in Qinxing Qingre Zhike Granule, namely geniposide, liquiritin, isoliquiritin, baicalin, wogonoside, baicalein, liquiritigenin, isoliquiritigenin and glycyrrhetinic acid. The analysis was performed on an Ultimate XB-C18 column at the flow rate of 0.4 mL min-1 in a single run of 18 min. The mobile phase was composed of 0.05% formic acid in water and acetonitrile with gradient elution. Positive and negative scanning and selected multiple reaction monitoring modes were applied for quantization. The proposed method showed good linearity in the given ranges from 0.6800-340.0 to 3.920-1960 ng mL-1 with r2 > 0.9917 for all the analytes. The precision (RSD) was no more than 12%, and the accuracy (RE) was less than ±11% for intra- and inter-day. The extract recovery and matrix effect were acceptable for the requirements of biological sample analysis. Moreover, the developed method was effectively applied to the pharmacokinetic investigation of Qinxing Qingre Zhike Granule after oral administration in rats.


Assuntos
Cromatografia Líquida/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Flavonoides/sangue , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Flavanonas , Flavonoides/química , Flavonoides/farmacocinética , Glucosídeos , Limite de Detecção , Modelos Lineares , Ratos , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Triterpenos/sangue , Triterpenos/química , Triterpenos/farmacocinética
18.
Phytomedicine ; 57: 396-402, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30849676

RESUMO

BACKGROUND: Willow bark (Salicis cortex) is a herbal medicinal drug used to treat fever and pain, such as headaches and lower back pain. Until now, it has not been fully understood which compounds are responsible for the efficacy of the drug. PURPOSE: Although salicylic acid is known as a metabolite of salicylic alcohol derivatives of willow bark in vivo, it has been shown in previous studies that its concentration is too low to account for the overall efficacy of Salicis cortex. The aim this study was to broaden the knowledge regarding phenolic phase-II metabolites after oral intake of a willow bark extract. STUDY DESIGN/METHODS: Serum samples of a human pharmacokinetic study (Salicis cortex extract intake corresponding to 240 mg of total salicin, 10 volunteers, 12 h fasting time, controlled diet low in phenolics, and 12 blood withdrawals over a period of 24 h) were analyzed by LC-ESI-MS. A library of 142 possible metabolites associated with salicylic alcohol derivatives, flavonoids, and proanthocyanidins was used to characterize possible metabolization products. Their structures were confirmed by LC-ESI-MS experiments with reference compounds after a cleavage reaction using glucuronidase and sulfatase as well as by LC-MS/MS experiments. RESULTS: In the serum samples, phase-II metabolites of naringenin (2x glucuronides, 2x sulfates, 2x mixed glucuronide-sulfates), eriodictyol (3x glucuronides, 1x sulfate), taxifolin (1x sulfate), catechin (1x sulfate, 1x mixed glucuronide sulfate), ferulic acid (1x sulfate), hydroxyphenyl-propionic acid (1x sulfate), dihydroxyphenyl-valerolactone (1x sulfate), saligenin (1x glucuronide, 1x sulfate), salicylic acid (1x sulfate, 1x unconjugated, 1x salicyluric acid), and catechol (1x glucuronide, 1x sulfate) were characterized. Because taxifolin, dihydroxyphenyl-valerolactone, ferulic acid, and hydroxyphenyl-propionic acid could not be detected in the willow bark preparation, they could be metabolization products of genuine flavanones and flavan-3-ols as well as coumaric acid or C-ring cleavage products of flavonoids, which were present in the extract. No phase-II metabolites of procyanidins and no genuine flavonoid glycosides were detected in all serum samples. CONCLUSION: This is the first study to identify human metabolites of flavonoids, proanthocyanidins and salicylic alcohol derivatives of Salicis cortex beside salicylic acid or catechol. For the most characterized metabolites, anti-inflammatory activity has been described in the literature, and the present results are an important step in understanding the anti-inflammatory efficacy of willow bark in vivo.


Assuntos
Casca de Planta/química , Extratos Vegetais/sangue , Extratos Vegetais/farmacocinética , Salix/química , Administração Oral , Álcoois Benzílicos/sangue , Álcoois Benzílicos/farmacocinética , Cromatografia Líquida , Flavonoides/sangue , Flavonoides/farmacocinética , Glicosídeos/análise , Glicosídeos/sangue , Glicosídeos/farmacocinética , Voluntários Saudáveis , Humanos , Inativação Metabólica , Extratos Vegetais/administração & dosagem , Espectrometria de Massas em Tandem
19.
Food Chem Toxicol ; 126: 15-24, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30738132

RESUMO

Morin is a flavonoid has been reported with several pharmacological effects such as, antioxidant, anti-inflammatory, anticancer, antidiabetic, etc. However, morin has low solubility in water, which decreases the bioavailability and limits its clinical application. In this way, to improve the pharmaceutical properties, morin was complexed in hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and its oral bioavailability and anti-inflammatory effects were evaluated. Initially, a phase solubility study was performed, which showed that HP-ß-CD would be the better cyclodextrin for the formation of complexes with morin. The morin/HP-ß-CD inclusion complex (1:1) was prepared by freeze-drying method. The sample obtained was characterized by DSC, FTIR, PXRD, SEM and 1H NMR techniques, evidencing the formation of morin/HP-ß-CD inclusion complex. In addition, complexation efficiency (98.3%) and loading content (17.63%), determined by HPLC demonstrated that morin was efficiently complexed in HP-ß-CD. In vitro dissolution study confirmed that morin/HP-ß-CD inclusion complex increased the solubility and dissolution rate of morin. The oral bioavailability of the morin/HP-ß-CD complex and free morin were evaluated through a pharmacokinetic study in rat plasma. The oral bioavailability of morin complexed with HP-ß-CD was increased by 4.20 times compared with the free morin. Hyperalgesia induced by carrageenan and carrageenan-induced pleurisy were carried out in mice to evaluate the antihyperalgesic and anti-inflammatory activities of free morin and inclusion complex. Morin/HP-ß-CD inclusion complex showed antihyperalgesic effect in inflammatory pain model and anti-inflammatory effect decreasing leukocyte migration and TNF-α levels at a lower dose than free morin. Therefore, the morin/HP-ß-CD inclusion complex improved the solubility, dissolution rate, oral bioavailability, antihyperalgesic and anti-inflammatory effects of morin. In this way, the morin/HP-ß-CD inclusion complex exhibits potential for development of new pharmaceutical product for future clinical applications.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Flavonoides/química , Flavonoides/farmacocinética , Hiperalgesia/tratamento farmacológico , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Animais , Anti-Inflamatórios/sangue , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Composição de Medicamentos , Flavonoides/sangue , Humanos , Hiperalgesia/sangue , Hiperalgesia/induzido quimicamente , Hipoglicemiantes/sangue , Masculino , Ratos , Ratos Wistar , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
20.
Artigo em Inglês | MEDLINE | ID: mdl-30743142

RESUMO

Detection and identification of the in vivo metabolites of traditional Chinese medicine by untargeted profiling strategies are often confronted with severe interference from complex endogenous substances. Here we developed an integral approach, by combining untargeted data-dependent MS2 (dd-MS2) of Q-Orbitrap mass spectrometry and predictive multiple reaction monitoring-information dependent acquisition-enhanced product ion scan (pMRM-IDA-EPI) of triple quadrupole-linear ion trap (QTRAP) mass spectrometry, aiming to detect and identify more extensive metabolites in bio-samples. Ecliptae Herba (EH) is a widely consumed medicinal herb with the effects of nourishing liver/kidney, but its metabolites in vivo have not been fully elucidated. Firstly, after UHPLC separation on an HSS T3 column, chemical fingerprinting of 70% ethanolic extract of EH was performed by untargeted dd-MS2 in negative ion mode. We could characterize 41 compounds from EH, and 24 were detectable in the plasma of rats (prototypes) after oral administration of EH extract (1 g/kg). Secondly, using echinocystic acid (triterpene), wedelolactone (coumarin), and apigenin (flavonoid) as the different parent templates, an MRM list containing 150 predicted ion-pairs was established to enhance MS2 scan by pMRM-IDA-EPI, which enabled the primary identification of up to 200 metabolites. The biotransformations mainly involve oxidation, hydrogenation, methylation, glucuronidation, sulfonation etc. Thirdly, the rat plasma samples obtained after oral administration of three pure compounds (echinocystic acid, wedelolactone and apigenin) were analyzed to verify the reliability of metabolites identification, and 11, 4, and 10 metabolites were found individually. This is the first comprehensive research on the metabolism of EH in vivo.


Assuntos
Cumarínicos/sangue , Medicamentos de Ervas Chinesas , Eclipta/química , Flavonoides/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Cumarínicos/metabolismo , Cumarínicos/farmacocinética , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Flavonoides/metabolismo , Flavonoides/farmacocinética , Hidroxibenzoatos/sangue , Hidroxibenzoatos/metabolismo , Hidroxibenzoatos/farmacocinética , Ratos
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