RESUMEN
Scutellarein is a flavonoid from Scutellaria baicalensis Georgi that has been shown to have a variety of pharmacological activities. This review aims to summarize the pharmacological and pharmacokinetic studies on scutellarein and provide useful information for relevant scholars. Pharmacological studies indicate that scutellarein possesses a diverse range of pharmacological properties, including but not limited to anti-inflammatory, antioxidant, antiviral, neuroprotective, hypoglycemic, hypolipidemic, anticancer, and cardiovascular protective effects. Further investigation reveals that the pharmacological effects of scutellarein are driven by multiple mechanisms. These mechanisms encompass the scavenging of free radicals, inhibition of the activation of inflammatory signaling pathways and expression of inflammatory mediators, inhibition of the activity of crucial viral proteins, suppression of gluconeogenesis, amelioration of insulin resistance, improvement of cerebral ischemia-reperfusion injury, induction of apoptosis in cancer cells, and prevention of myocardial hypertrophy, among others. In summary, these pharmacological studies suggest that scutellarein holds promise for the treatment of various diseases. It is imperative to conduct clinical studies to further elucidate the therapeutic effects of scutellarein. However, it is worth noting that studies on the pharmacokinetics reveal an inhibitory effect of scutellarein on uridine 5'-diphosphate glucuronide transferases and cytochrome P450 enzymes, potentially posing safety risks.
Asunto(s)
Apigenina , Humanos , Apigenina/farmacología , Apigenina/farmacocinética , Animales , Antioxidantes/farmacología , Antioxidantes/farmacocinética , Antiinflamatorios/farmacología , Antiinflamatorios/farmacocinética , Scutellaria baicalensis/química , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/farmacocinética , Hipoglucemiantes/farmacología , Hipoglucemiantes/farmacocinéticaRESUMEN
Dry eye disease (DED) is a chronic multifactorial disorder of the ocular surface caused by tear film dysfunction and constitutes one of the most common ocular conditions worldwide. However, its treatment remains unsatisfactory. While artificial tears are commonly used to moisturize the ocular surface, they do not address the underlying causes of DED. Apigenin (APG) is a natural product with anti-inflammatory properties, but its low solubility and bioavailability limit its efficacy. Therefore, a novel formulation of APG loaded into biodegradable and biocompatible nanoparticles (APG-NLC) was developed to overcome the restricted APG stability, improve its therapeutic efficacy, and prolong its retention time on the ocular surface by extending its release. APG-NLC optimization, characterization, biopharmaceutical properties and therapeutic efficacy were evaluated. The optimized APG-NLC exhibited an average particle size below 200 nm, a positive surface charge, and an encapsulation efficiency over 99 %. APG-NLC exhibited sustained release of APG, and stability studies demonstrated that the formulation retained its integrity for over 25 months. In vitro and in vivo ocular tolerance studies indicated that APG-NLC did not cause any irritation, rendering them suitable for ocular topical administration. Furthermore, APG-NLC showed non-toxicity in an epithelial corneal cell line and exhibited fast cell internalization. Therapeutic benefits were demonstrated using an in vivo model of DED, where APG-NLC effectively reversed DED by reducing ocular surface cellular damage and increasing tear volume. Anti-inflammatory assays in vivo also showcased its potential to treat and prevent ocular inflammation, particularly relevant in DED patients. Hence, APG-NLC represent a promising system for the treatment and prevention of DED and its associated inflammation.
Asunto(s)
Apigenina , Portadores de Fármacos , Síndromes de Ojo Seco , Lípidos , Nanopartículas , Animales , Apigenina/administración & dosificación , Apigenina/química , Apigenina/farmacología , Apigenina/farmacocinética , Portadores de Fármacos/química , Síndromes de Ojo Seco/tratamiento farmacológico , Humanos , Conejos , Lípidos/química , Lípidos/administración & dosificación , Línea Celular , Nanopartículas/química , Administración Oftálmica , Liberación de Fármacos , Antiinflamatorios/administración & dosificación , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/farmacocinética , Tamaño de la Partícula , Nanoestructuras/administración & dosificación , Nanoestructuras/química , MasculinoRESUMEN
The COVID-19 new variants spread rapidly all over the world, and until now scientists strive to find virus-specific antivirals for its treatment. The main protease of SARS-CoV-2 (Mpro) exhibits high structural and sequence homology to main protease of SARS-CoV (93.23% sequence identity), and their sequence alignment indicated 12 mutated/variant residues. The sequence alignment of SARS-CoV-2 main protease led to identification of only one mutated/variant residue with no significant role in its enzymatic process. Therefore, Mpro was considered as a high-profile drug target in anti-SARS-CoV-2 drug discovery. Apigenin analogues to COVID-19 main protease binding were evaluated. The detailed interactions between the analogues of Apigenin and SARS-CoV-2 Mpro inhibitors were determined as hydrogen bonds, electronic bonds and hydrophobic interactions. The binding energies obtained from the molecular docking of Mpro with Boceprevir, Apigenin, Apigenin 7-glucoside-4'-p-coumarate, Apigenin 7-glucoside-4'-trans-caffeate and Apigenin 7-O-beta-d-glucoside (Cosmosiin) were found to be -6.6, -7.2, -8.8, -8.7 and -8.0 kcal/mol, respectively. Pharmacokinetic parameters and toxicological characteristics obtained by computational techniques and Virtual ADME studies of the Apigenin analogues confirmed that the Apigenin 7-glucoside-4'-p-coumarate is the best candidate for SARS-CoV-2 Mpro inhibition.
Asunto(s)
Antivirales/farmacología , Apigenina/farmacología , Tratamiento Farmacológico de COVID-19 , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Secuencia de Aminoácidos , Antivirales/química , Antivirales/farmacocinética , Apigenina/química , Apigenina/farmacocinética , Bioingeniería , COVID-19/virología , Simulación por Computador , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/genética , Inhibidores de Cisteína Proteinasa/química , Inhibidores de Cisteína Proteinasa/farmacocinética , Evaluación Preclínica de Medicamentos , Glucósidos/química , Glucósidos/farmacocinética , Glucósidos/farmacología , Humanos , Simulación del Acoplamiento Molecular , Fitoterapia , Dominios Proteicos , SARS-CoV-2/genéticaRESUMEN
The intestinal capillary pathway is the most common way to absorb oral drugs, but for drugs with poor solubility and permeability and high first-pass metabolism, this pathway is very inefficient. Although intestinal lymphatic transport of lipophilic drugs or prodrugs is a promising strategy to improve the oral delivery efficiency of these drugs. The prodrug strategy for modifying compounds with Log P > 5 to promote intestinal lymphatic transport is a common approach. However, transport of poor liposoluble compounds (Log P < 0) through intestinal lymph has not been reported. Herein, triglyceride-mimetic prodrugs of scutellarin were designed and synthesized to promote intestinal lymphatic transport and increase oral bioavailability. Lymphatic transport and pharmacokinetic experiments showed that two prodrugs did promote intestinal lymphatic transport of scutellarin and the relative oral bioavailability was 2.24- and 2.45-fold of scutellarin, respectively. In summary, triglyceride-mimetic prodrugs strategy was used for the first time to study intestinal lymphatic transport of scutellarin with Log P < 0, which could further broaden the application range of drugs to improve oral bioavailability with the assistance of intestinal lymphatic transport.
Asunto(s)
Apigenina/farmacocinética , Transporte Biológico/fisiología , Glucuronatos/farmacocinética , Sistema Linfático/fisiología , Profármacos/química , Triglicéridos/química , Administración Oral , Animales , Apigenina/administración & dosificación , Química Farmacéutica , Estabilidad de Medicamentos , Femenino , Glucuronatos/administración & dosificación , Humanos , Ratas , Ratas Sprague-DawleyRESUMEN
Breviscapine is one of the extracts of several flavonoids of Erigeron breviscapus. Scutellarin is the main active component of breviscapine, and the qualitative or quantitative criteria as well. Scutellarin and its analogs share a similar skeleton of the flavonoids. Breviscapine has been widely used in the treatment of cerebral infarction and its sequelae, cerebral thrombus, coronary heart disease (CHD), and angina pectoris. Breviscapine has a broad spectrum of pharmacological activities, such as increasing blood flow, improving microcirculation, dilating blood vessels, decreasing blood viscosity, promoting fibrinolysis, inhibiting platelet aggregation, and thrombosis formation, etc. In addition, breviscapine and its analogs have significant value for drug research and development because of the superiority of those significant bioactivities. Furthermore, an increasing number of pharmacokinetic studies have explored the mechanism of scutellarin and its analogs. To provide a comprehensive understanding of the current research on breviscapine, scutellarin, and the analogs, the structural features, distribution situation, preparation method, content determination method, clinical applications, pharmacological action as well as pharmacokinetics are summarized in the present review.
Asunto(s)
Apigenina , Flavonoides , Glucuronatos , Extractos Vegetales , Apigenina/química , Apigenina/farmacocinética , Apigenina/farmacología , Flavonoides/química , Flavonoides/farmacocinética , Flavonoides/farmacología , Glucuronatos/química , Glucuronatos/farmacocinética , Glucuronatos/farmacología , Humanos , Estructura Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacocinética , Extractos Vegetales/farmacologíaRESUMEN
This work mainly studies the interfacial behaviors of scutellarin on a newly developed emulsion and establishes a three-phase distribution model. The results showed that the concentration of scutellarin could decrease the interfacial tension and the gel-liquid crystal phase transition temperature of phospholipids. By observing the micromorphology of the emulsion, it is inferred that the drug exists on the emulsion interface. The distribution of drugs in three phases at different pH was calculated. The results showed that when pH was in the range of 3.0-8.0, the content of scutellarin in the oil phase was less than 0.25%; when pH < 7.4, more than 88% of the drugs were on the interface; when pH > 7.4, the drugs were mainly distributed in the aqueous phase. Therefore, the behavior of emulsions (pH 6.0) in vitro and in vivo is mainly composed of the behavior of drugs on the interface. The study above can explain some properties of the emulsions after loading scutellarin. Including the decrease of particle size and stability constant Ke, the increase of zeta potential, and the decreased chemical stability after the pH value went higher.
Asunto(s)
Apigenina/administración & dosificación , Estabilidad de Medicamentos , Emulsiones/química , Glucuronatos/administración & dosificación , Apigenina/química , Apigenina/farmacocinética , Composición de Medicamentos , Emulsiones/farmacocinética , Glucuronatos/química , Glucuronatos/farmacocinética , Humanos , Concentración de Iones de Hidrógeno , Tensión SuperficialRESUMEN
The flavone apigenin (APG), alone as well as in combination with other chemotherapeutic agents, is known to exhibit potential anticancer effects in various tumors and inhibit growth and metastasis of melanoma. However, the potential of apigenin nanoparticles (APG-NPs) to prevent lung colonization of malignant melanoma has not been well investigated. APG-loaded PLGA-NPs were surface-functionalized with meso-2,3-dimercaptosuccinic acid (DMSA) for the treatment of melanoma lung metastasis. DMSA-conjugated APG-loaded NPs (DMSA-APG-NPs) administered by an oral route exhibited sustained APG release and showed considerable enhancement of plasma half-life, Cmax value, and bioavailability compared to APG-NPs both in plasma and the lungs. DMSA-conjugated APG-NPs showed comparably higher cellular internalization in B16F10 and A549 cell lines compared to that of plain NPs. Increased cytotoxicity was observed for DMSA-APG-NPs compared to APG-NPs in A549 cells. This difference between the two formulations was lower in B16F10 cells. Significant depolarization of mitochondrial transmembrane potential and an enhanced level of caspase activity were observed in B16F10 cells treated with DMSA-APG-NPs compared to APG-NPs as well. Western blot analysis of various proteins was performed to understand the mechanism of apoptosis as well as prevention of melanoma cell migration and invasion. DMSA conjugation substantially increased accumulation of DMSA-APG-NPs given by an intravenous route in the lungs compared to APG-NPs at 6 and 8 h. This was also corroborated by scintigraphic imaging studies with radiolabeled formulations administered by an intravenous route. Conjugation also allowed comparatively higher penetration as evident from an in vitro three-dimensional tumor spheroid model study. Finally, the potential therapeutic efficacy of the formulation was established in experimental B16F10 lung metastases, which suggested an improved bioavailability with enhanced antitumor and antimetastasis efficacy of DMSA-conjugated APG-NPs following oral administration.
Asunto(s)
Apigenina/farmacocinética , Portadores de Fármacos/química , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/patología , Animales , Apigenina/administración & dosificación , Apoptosis/efectos de los fármacos , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Liberación de Fármacos , Femenino , Humanos , Neoplasias Pulmonares/secundario , Melanoma/secundario , Ratones , Nanopartículas/química , Invasividad Neoplásica/prevención & control , Tamaño de la Partícula , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Neoplasias Cutáneas/tratamiento farmacológico , Esferoides Celulares , Succímero/química , Distribución TisularRESUMEN
BACKGROUND: Vitexin is a natural flavonoid compound with multiple pharmacological activities and is extracted from the leaves and seeds of Vitex negundo L. var. cannabifolia (Sieb. et Zucc.) Hand.-Mazz. However, the metabolite characterization of this component remains insufficient. OBJECTIVE: To establish a rapid profiling and identification method for vitexin metabolites in rat urine, plasma and faeces after oral administration using a UHPLC-Q-Exactive orbitrap mass spectrometer were coupled with multiple data-mining methods. METHODS: In this study a simple and rapid systematic strategy for the detection and identification of constituents was proposed based on UHPLC-Q-Exactive Orbitrap mass spectrometry in parallel reaction monitoring mode combining diagnostic fragment ion filtering techniques. RESULTS: A total of 49 metabolites were fully or partially characterized based on their accurate mass, characteristic fragment ions, retention times, corresponding ClogP values, and so on. It is obvious that C-glycosyl flavonoids often display an [M+H-120]+ ion that represents the loss of C4H8O4. As a result, these metabolites were presumed to be generated through glucuronidation, sulfation, deglucosylation, dehydrogenation, methylation, hydrogenation, hydroxylation, ring cleavage and their composite reactions. Moreover, the characteristic fragmentation pathways of flavonoids, chalcones and dihydrochalcones were summarized for the subsequent metabolite identification. CONCLUSION: The current study provided an overall metabolic profile of vitexin which will be of great help in predicting the in vivo pharmacokinetic profiles and understanding the action mechanism of this active ingredient.
Asunto(s)
Apigenina/metabolismo , Administración Oral , Animales , Apigenina/administración & dosificación , Apigenina/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Minería de Datos , Heces/química , Masculino , Metabolómica/métodos , Modelos Animales , Ratas , Ratas Sprague-Dawley , Espectrometría de Masas en Tándem/métodos , Orina/química , Vitex/químicaRESUMEN
BACKGROUND: Apigenin, a natural plant flavone, has been shown to possess a variety of biological properties. OBJECTIVE: In this report, a highly selective and sensitive LC-MS/MS method was developed and validated for the determination of apigenin in rat plasma. METHODS: Analysts were separated on the HSS T3 column (1.8 µm 2.1×100 mm) using acetonitrile and 0.1% formic acid in 2mM ammonium acetate buffer at a supply rate of 0.200 mL/min as eluent in gradient model. RESULTS: Plasma samples were treated by protein precipitation using acetonitrile for the recovery ranging from 86.5% to 90.1% for apigenin. The calibration curves followed linearity in the concentration range of 0.50-500ng/mL. The inter-day and intra-day precisions at different QC levels within 13.1% and the accuracies ranged from -10.6% to 8.6%. CONCLUSION: The assay has been successfully applied to the pharmacokinetic study of apigenin in rats.
Asunto(s)
Apigenina/sangre , Apigenina/farmacocinética , Espectrometría de Masas en Tándem/métodos , Animales , Cromatografía Liquida/métodos , Masculino , Plasma , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los ResultadosRESUMEN
Scutellarin is the major and active constituent of Dengzhan Xixin Injection (DZXX), a traditional Chinese medicine prepared from the aqueous extract of Erigeron breviscapus and widely used for the treatment of various cerebrovascular diseases in clinic. In present study, the possible pharmacokinetic differences of scutellarin after intravenous administration of scutellarin alone or DZXX were explored. Additional, the potential roles of ß-glucuronidase (GLU) and OATP2B1 in drug-drug interaction (DDI) between scutellarin and constituents of DZXX were further evaluated in vitro. The plasma concentration, urinary and biliary excretion of scutellarin in rats after administration of DZXX, were significantly higher than those received scutellarin, while pharmacokinetic profile of Apigenin 7-O-glucuronide (AG) in rats was similar no matter AG or DZXX group. Furthermore, higher concentration in brain and plasma, however, lower level of scutellarin in intestine were observed after intravenous administration of DZXX. Finally, AG and caffeoylquinic acid esters were found to significantly inhibit GLU and OATP2B1 in vitro, which might explain, at least in part, the pharmacokinetic DDI between scutellarin and other chemical constituents in DZXX. The findings provided deep insight into the prescription-formulating principle in DZXX for treating the cerebrovascular diseases.
Asunto(s)
Apigenina/farmacocinética , Erigeron , Glucuronatos/farmacocinética , Glucuronidasa/metabolismo , Transportadores de Anión Orgánico/metabolismo , Extractos Vegetales/farmacocinética , Animales , Apigenina/sangre , Apigenina/orina , Bilis/química , Composición de Medicamentos , Interacciones Farmacológicas , Endocitosis , Glucuronatos/sangre , Glucuronatos/orina , Glucuronidasa/antagonistas & inhibidores , Células HEK293 , Humanos , Hidrólisis , Inyecciones Intravenosas , Masculino , Transportadores de Anión Orgánico/antagonistas & inhibidores , Ratas Sprague-Dawley , Distribución TisularRESUMEN
A rapid and sensitive ultra high performance liquid chromatography with tandem mass spectrometry method was established and validated for simultaneous determination of thirteen bioactive components (gallic acid, protocatechuic acid, puerarin, p-hydroxycinnamic acid, daidzin, ononin, daidzein, naringenin, genistein, apigenin, formononetin, biochanin A, and ß-sitosterol) of Radix Puerariae extract in rat plasma and tissues. The plasma and tissues samples were pretreated by protein precipitation extraction, and umbelliferone and rutin were used as internal standards. Sample separation was performed on a ZORBAX RRHD Eclipse plus C18 column (2.1 mm × 50 mm, 1.8 µm, Agilent) with a mobile phase consisting of methanol-water (containing 0.1% formic acid). The mass spectrometry analysis was conducted in positive and negative ionization modes with multiple reaction monitoring. The lower limit of quantitation range for the 13 analytes was 0.2-35 ng/mL. The intra- and inter-day precision of all the analytes were less than 10.92%, with an accuracy ranging from -13.10 to 11.96%. Both the recovery and matrix effect were within acceptable limits. This method was successfully applied to pharmacokinetic and tissue distribution study of the 13 bioactive components in rats after oral administration of R. Puerariae extract.
Asunto(s)
Apigenina/farmacocinética , Medicamentos Herbarios Chinos/farmacocinética , Genisteína/farmacocinética , Isoflavonas/farmacocinética , Pueraria/química , Sitoesteroles/farmacocinética , Administración Oral , Animales , Apigenina/administración & dosificación , Apigenina/análisis , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/análisis , Genisteína/administración & dosificación , Genisteína/análisis , Isoflavonas/administración & dosificación , Isoflavonas/análisis , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Sitoesteroles/administración & dosificación , Sitoesteroles/análisis , Espectrometría de Masas en Tándem , Distribución TisularRESUMEN
Apigenin is a flavonoid of low toxicity and multiple beneficial bioactivities. Published reviews all focused on the findings using eukaryotic cells, animal models, or epidemiological studies covering the pharmacokinetics, cancer chemoprevention, and drug interactions of apigenin; however, no review is available on the antimicrobial effects of apigenin. Research proves that dietary apigenin passes through the upper gastrointestinal tract and reaches the colon after consumption. For that reason, it is worthwhile to study the potential interactions between apigenin and human gut microbiota. This review summarizes studies on antimicrobial effects of apigenin as well as what has been reported on apigenin and human gut microbiota. Various levels of effectiveness have been reported on apigenin's antibacterial, antifungal, and antiparasitic capability. It has been shown that apigenin or its glycosides are degraded into smaller metabolites by certain gut bacteria which can regulate the human body after absorption. How apigenin contributes to the structural and functional changes in human gut microbiota as well as the bioactivities of apigenin bacterial metabolites are worth further investigation.
Asunto(s)
Antiinfecciosos/uso terapéutico , Apigenina/uso terapéutico , Flavonoides/uso terapéutico , Microbioma Gastrointestinal/efectos de los fármacos , Animales , Antiinfecciosos/farmacocinética , Apigenina/farmacocinética , Bacterias/efectos de los fármacos , Suplementos Dietéticos , Flavonoides/farmacocinética , Humanos , Neoplasias/dietoterapiaRESUMEN
A new ultra-high performance liquid chromatography-mass spectrometry-mass spectrometry (UHPLC-MS/MS) system has been formulated for the resolution of closely related drugs apigenin (API, a bioflavinoid) and prednisolone (PRD) from their mixture. This developed method comprised of a "BEH™ C18 column (50â¯mmâ¯×â¯2.1â¯mm, 1.7⯵m)" using acetonitrile and 0.1% formic acid (35:65â¯v/v) at a supply rate of 0.25â¯mL·min-1 as eluent. It was found that selected eluent provided short run time (≤2.5â¯min) as well as better peak symmetry. Satisfactory values of chromatographic parameters such as resolution (Rsâ¯=â¯2.5), capacity factor (k; 13.6 and 23.4 for API and PRD respectively, selectivity (αâ¯=â¯1.72) and number of theoretical plates (N; 3789 and 42,435 for API and PRD respectively) indicate the efficiency of the developed method. The obtained separation was then exploited for the detection and measurement of API in rat plasma sample by means of PRD as an "internal standard" (IS). The eluted compounds in plasma were identified by tandem mass spectrometry by means of tandem quadrupole (TQ) detector ("Waters Corp., Milford, MA") fortified with an "electrospray ionisation (ESI)" source functioning in positive ionization mode. The determination of API in plasma was accomplished by means of "multiple reactions monitoring (MRM)" mode. Assortment of "ionization pairs" (m/z) was displayed in the following manner: API: 270.99â¯ââ¯152.9 ("cone voltage" 57â¯V, "collision energy" 34â¯V), PRD: 403.172â¯ââ¯385.224 ("cone voltage" 42â¯V, "collision energy" 13â¯V). The calibration curves followed linearity in concentration range of 05-1000â¯ngâ¯mL-1 with limit of detection "LOD" and limit of quantification "LOQ" of 7.30 and 22.77â¯ngâ¯mL-1, respectively. The developed method was validated taking into consideration various test conditions and satisfactory values of various parameters such as linearity (r2⯱â¯SDâ¯=â¯0.9995⯱â¯0.0005), interday accuracy (88-120%), interday precision % RSDâ¯=â¯3.30-13.65% whereas intraday accuracy (91-118%) intraday precision % RSDâ¯=â¯1.18-5.83) indicated its validity. The validation outcomes fulfilled the standards of united states food and drug administration "USFDA" in addition Scientific Working Group for Forensic Toxicology "SWGTOX" guiding principles and were not beyond the tolerable constraint. The process developed in plasma was efficaciously harnessed in the pharmacokinetic investigation of various formulations of API after oral administration in rats.
Asunto(s)
Apigenina/aislamiento & purificación , Apigenina/farmacocinética , Cromatografía Líquida de Alta Presión/métodos , Prednisolona/aislamiento & purificación , Animales , Apigenina/sangre , Estabilidad de Medicamentos , Límite de Detección , Modelos Lineales , Masculino , Prednisolona/sangre , Ratas , Ratas Wistar , Reproducibilidad de los Resultados , Espectrometría de Masas en Tándem/métodosRESUMEN
Co-crystals have received increasing attention during the past decades for their ability to modify the solubility and other physicochemical properties of active pharmaceutical ingredients. Apigenin (Agn) and Daidzein (Dai) are flavonoid compounds with a variety of biological effects. However, the bioavailability and clinical applications of flavonoid compounds are usually limited by their poor aqueous solubilities. In this study, theophylline (Thp) is used as a coformer to co-crystallize with Agn and Dai. The solid-state properties of the co-crystals of Thp with Agn and Dai are characterized by powder X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, Raman spectroscopy, and nuclear magnetic resonance experiments. In addition, both co-crystals show a greater resistance to hydration than Thp alone. The solubilities, intrinsic dissolution rates, and permeabilities of Agn-Thp co-crystal and Dai-Thp co-crystal are improved compared with those of parent flavonoids. The pharmacokinetic study shows that the bioavailabilities of both co-crystals are enhanced in comparison with the corresponding physical mixtures and parent flavonoids. This study demonstrates that the co-crystallization by using theophylline is a promising strategy to improve physicochemical properties and bioavailability of flavonoid compounds.
Asunto(s)
Apigenina/farmacocinética , Química Farmacéutica , Composición de Medicamentos/métodos , Isoflavonas/farmacocinética , Teofilina/farmacocinética , Administración Oral , Animales , Apigenina/administración & dosificación , Apigenina/química , Disponibilidad Biológica , Rastreo Diferencial de Calorimetría , Cristalización , Isoflavonas/administración & dosificación , Isoflavonas/química , Espectroscopía de Resonancia Magnética , Masculino , Polvos , Ratas , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Espectrometría Raman , Teofilina/administración & dosificación , Teofilina/química , Difracción de Rayos XRESUMEN
Xanthii fructus (XF), the fruit of Xanthium sibiricum Patr., is a traditional Chinese materia medica commonly used to treat allergic rhinitis and other rhinitis diseases. To uncover the mechanism of the stir-frying process and its effect on the pharmacokinetic behavior of active compounds in model rats, four active compounds-chlorogenic acid, 4-caffeoylquinic acid, 1,5-O-dicaffeoylquinic acid and apigenin-were selected based on previous spectrum-effect experiments. High performance liquid chromatography tandem triple quadrupole mass spectrometry (UPLC-QqQ-MS) technology, an accurate and feasible method, was applied to measure the concentration of these four compounds in rat plasma. This validated method can accurately measure the concentration of each compound at each sampling point of rat plasma. This validated method shows good linearity, extraction recoveries, matrix effects, intra- and inter-day precision and stabilities. Compared with the XF group, the maximum plasma concentration (Cmax ) value of 1,5-O-dicaffeoylquinic acid decreased remarkably (p < 0.05) after oral administration of stir-fried Xanthii fructus (SXF) extract, while the other compounds showed no significant difference. The mean residence time value of chlorogenic acid (p < 0.05) and 1,5-O-dicaffeoylquinic acid (p<0.01) after oral administration of SXF extraction demonstrated significant differences compared with the XF group, while the other two compounds showed no statistical difference, indicating that the stir-frying process prolonged the effect time and delayed the removal time of chlorogenic acid and 1,5-O-dicaffeoylquinic acid. The values of the area under the plasma concentration-time curve from zero to the last quantifiable time-point, the area under the plasma concentration-time curve from zero to infinity, the time to maximum concentration and the elimination half-life of four compounds in the SXF group showed no statistically significant difference from the XF group. From this data, we speculated that the stir-frying process can not only keep the absorption of 4-caffeoylquinic acid and apigenin, but also increase the effect time of chlorogenic acid and 1,5-O-dicaffeoylquinic acid, which could be the mechanism underlying the stir-frying process enhancing the effects of XF.
Asunto(s)
Apigenina/sangre , Cromatografía Líquida de Alta Presión/métodos , Cinamatos/sangre , Medicamentos Herbarios Chinos/farmacocinética , Espectrometría de Masas en Tándem/métodos , Administración Oral , Animales , Apigenina/química , Apigenina/farmacocinética , Cinamatos/química , Cinamatos/farmacocinética , Estabilidad de Medicamentos , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Límite de Detección , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVES: The isolation and identification of the flavonoids present in a decoction of Desmodium adscendens was performed. In view of the oral use of the decoction, this work focused on the stability in gastrointestinal conditions and biotransformation by intestinal microflora in the colon of D-pinitol, vitexin and the flavonoid fraction of the decoction, as a first step in unravelling its behaviour in the human body. METHODS: The freeze-dried decoction was first subjected to column chromatography. Subsequently an enriched flavonoid fraction, was separated by repeated semi-preparative high-performance liquid chromatography (HPLC) or by HPLC-SPE. The isolated compounds were elucidated by NMR. Biotransformation experiments were carried in an in vitro gastrointestinal dialysis model. KEY FINDINGS: The major flavonoids of a decoction of D. adscendens were characterized as vicenin-2, isoschaftoside, schaftoside, 2â³-O-xylosylvitexin, 2â³-O-pentosyl-C-hexosyl apigenin and a O-hexosyl-C-hexosyl apigenin, tentatively identified as 2â³-O-glucosyl-vitexin. During their passage in the gastrointestinal dialysis model, vitexin and C-glycosides thereof were found to be stable. Only the O-glycosidic bonds of O-glycosides of vitexin or isovitexin were hydrolysed during the colonic phase. CONCLUSIONS: A D. adscendens decoction was found to be rich in vitexin and isovitexin glycosides from which vitexin and the C-glycosides thereof were found to be stable in the simulated gastrointestinal tract.
Asunto(s)
Apigenina/farmacocinética , Fabaceae/química , Flavonoides/farmacocinética , Inositol/análogos & derivados , Apigenina/aislamiento & purificación , Biotransformación , Flavonoides/química , Flavonoides/aislamiento & purificación , Técnicas In Vitro , Inositol/aislamiento & purificación , Inositol/farmacocinética , Modelos Teóricos , Estructura Molecular , Hojas de la Planta/químicaRESUMEN
Erigeron breviscapus, a traditional Chinese medicine, is clinically used for the treatment of occlusive cerebral vascular diseases. We developed a sensitive and reliable ultra-performance liquid chromatography-electrospray-tandem mass spectrometry (UPLC-ESI-MS/MS) method for simultaneous quantitation of chlorogenic acid, scutellarin, and scutellarein, the main active constituents in Erigeron breviscapus, and compared the pharmacokinetics of these active ingredients in sham-operated and middle cerebral artery occlusion (MCAO) rats orally administrated with Erigeron breviscapus extract. Plasma samples were collected at 15 time points after oral administration of the Erigeron breviscapus extract. The levels of chlorogenic acid, scutellarin, and scutellarein in rat plasma at various time points were determined by a UPLC-ESI-MS/MS method, and the drug concentration versus time plots were constructed to estimate pharmacokinetic parameters. The concentration of chlorogenic acid in the plasma reached the maximum plasma drug concentration in about 15 min and was below the limit of detection after 4 h. Scutellarin and scutellarein showed the phenomenon of multiple absorption peaks in sham-operated and MCAO rats, respectively. Compared with the sham-operated rats, the terminal elimination half-life of scutellarein in the MCAO rats was prolonged by more than two times and the area under the curve of each component in the MCAO rats was significantly increased. The results showed chlorogenic acid, scutellarin, and scutellarein in MCAO rats had higher drug exposure than that in sham-operated rats, which provided a reference for the development of innovative drugs, optimal dosing regimens, and clinical rational drug use.
Asunto(s)
Apigenina/farmacocinética , Ácido Clorogénico/farmacocinética , Cromatografía Líquida de Alta Presión , Glucuronatos/farmacocinética , Extractos Vegetales/farmacocinética , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Administración Oral , Animales , Estabilidad de Medicamentos , Erigeron/química , Masculino , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Ratas , Sensibilidad y EspecificidadRESUMEN
Eclipta alba (Bhringraj) in ayurveda has been widely used as a traditional medicine for its multi-therapeutic properties for ages. Luteolin (LTL), wedelolactone (WDL) and apigenin (APG) are the three main bioactive phytochemicals present in Eclipta alba extract. However there was a lack of sensitive bioanalytical method for the pharmacokinetics of these free compounds in plasma which majorly contributes for their activities after oral administration of Eclipta alba. The present study aims to develop a sensitive, rapid and reliable liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous estimation of mice plasma concentrations of LTL, WDL and APG using quercetin as an internal standard for the pharmacokinetic analysis. Analytes were separated on Phenomenex Luna C18 (150â¯×â¯4.6â¯mm, 3.0⯵m) column with mobile phase containing methanol: acetonitrile (90: 10, v/v) and 0.1% formic acid in 10â¯mM ammonium formate buffer in the ratio of 70: 30 (v/v) in isocratic mode. Liquid-liquid extraction was optimized using Hansen solubility parameters and diethyl ether finalized as an extraction solvent for the recovery ranging from 61 to 76% for all analytes in mice plasma. The validated method has an accuracy and precision over the linearity range of 0.1-200â¯ng/mL with a correlation coefficient (r2) of ≥0.997. The intra and inter-day assay accuracy was between 98.17 and 107% and 95.83-107.89% respectively and the intra and inter day assay precision ranged from 0.37-6.05% and 1.85-10.76%, respectively for all the analytes. This validated method can be used for future clinical investigation studies of Eclipta alba extracts.
Asunto(s)
Apigenina/sangre , Cumarinas/sangre , Eclipta/química , Extracción Líquido-Líquido/métodos , Luteolina/sangre , Extractos Vegetales/farmacocinética , Animales , Apigenina/química , Apigenina/aislamiento & purificación , Apigenina/farmacocinética , Cloroformo , Cromatografía Liquida/métodos , Cumarinas/química , Cumarinas/aislamiento & purificación , Cumarinas/farmacocinética , Límite de Detección , Modelos Lineales , Luteolina/química , Luteolina/aislamiento & purificación , Luteolina/farmacocinética , Ratones , Extractos Vegetales/química , Reproducibilidad de los Resultados , Solubilidad , Espectrometría de Masas en Tándem/métodosRESUMEN
Apigenin trimethyl ether (5,7,4'-trimethoxyflavone, ATE), one of the key polymethoxyflavones present in black ginger (rhizome of Kaempferia parviflora) possesses various health-promoting activities. To optimize its medicinal application, the pharmacokinetics of ATE was assessed in Sprague-Dawley rats with emphases to identify the impacts from dose and repeated dosing on its major pharmacokinetic parameters. Plasma ATE levels were monitored by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. Upon single intravenous administration (2â¯mg/kg), plasma levels of ATE declined through an apparent first-order process while dose-escalation to 4 and 8â¯mg/kg led to its non-linear disposition, which could be described by the Michaelis-Menten model. Similarly, dose-dependent oral pharmacokinetics was confirmed and when the dose was escalated from 5 to 15 and 45â¯mg/kg, much longer mean residence time (MRT0âlast), higher dose-normalized maximal plasma concentration (Cmax/Dose) and exposure (AUC/Dose) were observed at 15 and/or 45â¯mg/kg. One-week daily oral administration of ATE at 15â¯mg/kg caused its accelerated elimination and the plasma exposure (AUC) after intravenous (2â¯mg/kg) and oral administration (15â¯mg/kg) dropped ~40 and 60%, respectively. As ATE displayed both dose- and time-dependent pharmacokinetics, caution is needed in the medicinal applications of ATE and/or black ginger.
Asunto(s)
Apigenina/farmacocinética , Éteres/farmacocinética , Administración Oral , Animales , Apigenina/administración & dosificación , Apigenina/sangre , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Éteres/administración & dosificación , Éteres/sangre , Masculino , Ratas Sprague-Dawley , ZingiberaceaeRESUMEN
A simple and rapid liquid chromatography-tandem mass spectrometry method was firstly developed for simultaneous quantification of neomangiferin, mangiferin, regaloside A, regaloside I, timosaponin BII, anemarsaponin E and timosaponin AIII in rat plasma after oral administration of Baihe Zhimu decoction, which plays an important role for the treatment of depression. The plasma samples were pretreated by a one-step direct protein precipitation with methanol. Separation of the seven components and scutellarin (IS) from endogenous components with high selectivity and sensitivity (LLOQ, 0.1-1.0ng/mL) was achieved within 10min using Poroshell 120 EC-C18 column (150mm×3.0mm, 2.7µm). A gradient mobile phase consisting of acetonitrile and water (containing 5mM ammonium acetate) was applied at a flow rate of 0.4mL/min. Detection and measurement were performed on an AB Sciex QTRAP® 5500 mass spectrometer in multiple reactions monitoring mode. The intra- and inter-day precisions were all within 15% and the accuracies were in the range of -10.4% to 14.5%. The recovery ranged from 90.8 to 113.8%. The validated method was successfully applied to pharmacokinetic study of the seven components in normal and chronic unpredicted mild stress-induced depression model rats.