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Frailty develops due to multiple factors, such as sarcopenia, chronic pain, and dementia. Go-sha-jinki-Gan (GJG) is a traditional Japanese herbal medicine used for age-related symptoms. We have reported that GJG improved sarcopenia, chronic pain, and central nervous system function through suppression of tumor necrosis factor-alpha (TNF-α) production. In the present study, GJG was found to reduce the production of TNF-α in the soleus muscle of senescence-accelerated mice at 12 weeks and 36 weeks. GJG did not change the differentiation of C2C12 cells with 2% horse serum. GJG significantly decreased the expression of Muscle atrophy F-box protein (MAFbx) induced by TNF-α in C2C12 cells on real-time PCR. TNF-α significantly decreased the expression of PGC-1α and negated the enhancing effect of GJG for the expression of PGC-1α on digital PCR. Examining 20 chemical compounds derived from GJG, cinnamaldehyde from cinnamon bark and Chikusetsusaponin V (CsV) from Achyrantes Root dose-dependently decreased the production of TNF-⺠in RAW264.7 cells stimulated by LPS. CsV inhibited the nuclear translocation of nuclear factor-kappa B (NF-κB) p65 in RAW264.7 cells. CsV showed low permeability using Caco-2 cells. However, the plasma concentration of CsV was detected from 30 min to 6 h and peaked at 1 h in the CD1 (ICR) mice after a single dose of GJG. In 8-week-old SAMP8 mice fed 4% (w/w) GJG from one week to four weeks, the plasma CsV concentration ranged from 0.0500 to 10.0 ng/mL. The evidence that CsV plays an important role in various anti-aging effects of GJG via suppression of TNF-⺠expression is presented.
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Envejecimiento/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Saponinas/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Transporte Activo de Núcleo Celular/efectos de los fármacos , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Medicamentos Herbarios Chinos/química , Masculino , Ratones , Ratones Endogámicos ICR , Proteínas Musculares/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Células RAW 264.7 , Proteínas Ligasas SKP Cullina F-box/metabolismo , Saponinas/administración & dosificación , Saponinas/sangre , Solubilidad , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ninjin'yoeito (NYT), a Japanese traditional Kampo medicine, has been reported to exert various clinical benefits such as relief from fatigue, malaise, anorexia, frailty, sarcopenia, and cognitive dysfunction. Recently, some review articles described the pharmacological effects of NYT and additionally indicated the possibility that multiple ingredients in NYT contribute to these effects. However, pharmacokinetic data on the ingredients are essential in addition to data on their pharmacological activities to accurately determine the active ingredients in NYT. AIM OF THE STUDY: This study assessed the in vivo pharmacokinetics of NYT using mice. MATERIALS AND METHODS: Target liquid chromatography-mass spectrometry (LC-MS) and wide target LC-MS or LC-tandem MS of NYT ingredients in plasma and the brain after oral administration of NYT were performed. Imaging MS was performed to investigate the detailed brain distributions of NYT ingredients. RESULTS: The concentrations of 13 ingredients in plasma and schizandrin in the brain were quantified via target LC-MS, and the wide target analysis illustrated that several ingredients are absorbed into blood and transported into the brain. Imaging MS revealed that schizandrin was homogenously dispersed in the NYT-treated mouse brain. CONCLUSION: These results should be useful for clarifying the active ingredients of NYT and their mechanisms of actions.
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Encéfalo/metabolismo , Ciclooctanos/farmacocinética , Medicamentos Herbarios Chinos/farmacocinética , Lignanos/farmacocinética , Compuestos Policíclicos/farmacocinética , Administración Oral , Animales , Cromatografía Liquida , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Masculino , Espectrometría de Masas , Ratones , Ratones Endogámicos C57BL , Distribución TisularRESUMEN
Shimotsuto is a traditional Japanese Kampo medicine used to treat gynecological diseases, such as irregular menstruation, in addition to oversensitivity to cold and chilblains. Part of the pharmacological actions of shimotsuto is traditionally considered to be exerted by an improvement effect of the blood and the circulatory system. Multiple ingredients (e.g., catalpol and paeoniflorin) contained in shimotsuto have been reported to have pharmacological activities on the blood and circulatory system, and thus been considered to contribute to the pharmacological actions of shimotsuto. However, it remains unclear whether the ingredients can be absorbed into the body following oral administration of shimotsuto. The aim in the present study was to specify shimotsuto ingredient absorbed into the systemic circulation in rats. Seven candidate active ingredients (catalpol, paeoniflorin, albiflorin, ligustilide, senkyunolide A, butylphthalide, and ferulic acid) in plasma after oral administration of shimotsuto were quantified by targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. This study also performed nontargeted LC-MS/MS analysis of plasma following administration of constituent crude drugs of shimotsuto to find extensively blood-absorbed ingredients of shimotsuto. Among detected peaks in the nontargeted analysis, two peaks could be identified as bergapten and 8-debenzoylpaeoniflorin, subsequently their concentrations in shimotsuto-treated rat plasma were quantified. These pharmacokinetic studies indicated that catalpol showed the highest plasma concentration following administration of shimotsuto, followed by 8-debenzoylpaeoniflorin. This study suggests that all nine ingredients are absorbed into the blood following oral administration of shimotsuto and possibly contribute to its pharmacological action.
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Cromatografía Líquida de Alta Presión/métodos , Enfermedades de los Genitales Femeninos/tratamiento farmacológico , Medicina Kampo/métodos , Espectrometría de Masas en Tándem/métodos , Animales , Femenino , Japón , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The Japanese traditional medicine maobushisaishinto (MBST) has been prescribed for treating upper respiratory tract infections, such as a common cold. However, its mode of action is poorly understood, especially concerning the MBST constituent Asiasari Radix (AR). In this study, we focused on AR, with an objective of clarifying its bioavailable active ingredients and role within MBST by performing pharmacokinetic and pharmacological studies. Firstly, we performed qualitative non-targeted analysis utilizing high-resolution mass spectrometry to explore the bioavailable ingredients of AR as well as quantitative targeted analysis to reveal plasma concentrations following oral administration of MBST in rats. Secondly, we performed in vitro pharmacological study of bioavailable AR ingredients in addition to other ingredients of MBST to confirm any agonistic activities against transient receptor potential (TRP) channels. As a result, methyl kakuol and other compounds derived from AR were detected in the rat plasma and showed agonistic activity against TRPA1. This study suggests that methyl kakuol as well as other compounds have the potential to be an active ingredient in AR and thus presumably would contribute in part to the effects exerted by MBST.
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Medicamentos Herbarios Chinos/química , Espectrometría de Masas en Tándem/métodos , Canales de Potencial de Receptor Transitorio/química , Animales , Cromatografía Líquida de Alta Presión , Medicamentos Herbarios Chinos/análisis , Medicamentos Herbarios Chinos/metabolismo , Semivida , Masculino , Medicina Tradicional , Óxido Nítrico/metabolismo , Plantas Medicinales/química , Plantas Medicinales/metabolismo , Ratas , Ratas Sprague-Dawley , Canales de Potencial de Receptor Transitorio/metabolismoRESUMEN
Geissoschizine methyl ether (GM) is one of the main active ingredients responsible for ameliorating the behavioral and psychological symptoms of dementia (BPSD) in Kampo medicine yokukansan. GM is mainly metabolized into hydroxylated forms (HM-1/2). However, the brain distributions of GM and HM has not been reported in vivo. In this study, therefore, the plasma concentrations and brain distribution of these compounds were examined in vivo using rats injected intravenously with GM. Plasma concentrations were analyzed using liquid chromatography-tandem mass spectrometry analysis and brain distribution using mass spectrometry imaging analysis. Plasma GM and HM-1 concentrations decreased in the 4 h after injection, whereas the concentration of plasma HM-2 increased at 4 h. In the 0.25 h-brain, GM signals were diffusely observed throughout the brain, including the cerebral cortex, hippocampus, striatum, thalamus, amygdala, cerebellum, and cerebral ventricle. HM signals were detected only in the ventricles of the brain at 4 h. These results suggest that plasma GM enters the brain and distributes in the parenchyma of various brain regions involved in BPSD, while plasma HM does not enter the brain parenchyma. This study is also the first to visually demonstrate the brain distribution of GM and its metabolite in vivo.
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Encéfalo , Alcaloides Indólicos , Espectrometría de Masas , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Demencia/diagnóstico por imagen , Demencia/tratamiento farmacológico , Demencia/metabolismo , Femenino , Alcaloides Indólicos/farmacocinética , Alcaloides Indólicos/farmacología , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
OBJECTIVES: The purpose of this study was to elucidate the association of cerebral large artery disease (CLAD) with cerebral blood flow (CBF) in the posterior cerebral artery (PCA) territory and cognitive performance. METHOD: We prospectively registered patients with CLAD who had internal carotid or middle cerebral artery (MCA) with the degree of stenosis ≥50%. Automated brain segmentation was used to quantify CBF in the thalamus, hippocampus, and PCA and MCA territories. We measured cognitive function of patients using the Wechsler Memory Scale Revised (WMS-R), the Mini-Mental State Examination (MMSE), and the Montreal Cognitive Assessment. Patients were divided into 3 groups according to CBF of the cortical and subcortical PCA territory. RESULTS: There were 60 patients included in this study. The degree of stenosis was significantly correlated with CBF in the PCA territory (Γâ¯=â¯0.35, Pâ¯=â¯.006) and hippocampus (Γâ¯=â¯0.34, Pâ¯=â¯.008). Verbal memory, general memory, and reproduction on WMS-R and MMSE were significantly reduced areas with low CBF in the PCA territory compared with areas with middle and high CBF. CONCLUSIONS: CBF of the PCA territory was significantly inversely correlated with the degree of stenosis in CLAD patients. Low CBF of the PCA territory was significantly associated with reduced cognitive and memory functions.
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Enfermedades Arteriales Cerebrales/psicología , Circulación Cerebrovascular/fisiología , Cognición/fisiología , Arteria Cerebral Posterior/fisiopatología , Anciano , Anciano de 80 o más Años , Estenosis Carotídea/fisiopatología , Estenosis Carotídea/psicología , Enfermedades Arteriales Cerebrales/fisiopatología , Femenino , Hemodinámica/fisiología , Hipocampo/irrigación sanguínea , Humanos , Masculino , Memoria/fisiología , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tálamo/irrigación sanguíneaRESUMEN
1. Yokukansankachimpihange (YKSCH), a Kampo formulation combining Citrus unshiu peel (CUP) and Pinellia tuber (PT) with yokukansan (YKS), has been recently used to treat the behavioral and psychological symptoms of dementia. Several flavonoids derived from CUP and PT reportedly exhibit psychopharmacological activity, but it remains unclear whether these flavonoids reach the brain after oral administration of YKSCH. 2. In this study, we first measured eight target flavonoids in the plasma and brain in rats orally administered YKSCH. Among these flavonoids, hesperidin, narirutin, nobiletin, and heptamethoxyflavone (HMF) were detected in the plasma, and nobiletin and HMF were detected in the brain. 3. Next, to clarify whether CUP and PT affect the pharmacokinetics of YKS ingredients in YKSCH, the plasma pharmacokinetics of geissoschizine methyl ether (GM) as a representative active ingredient in YKS was examined in rats orally administered YKSCH or YKS. There was no significant difference between the two groups, inferring that the pharmacokinetics of GM may not be affected by the two additional crude drugs. 4. Taken together, this study suggests that the CUP-derived flavonoids nobiletin and HMF may be responsible for the psychopharmacological effects of YKSCH in addition to YKS ingredients.
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Encéfalo/metabolismo , Medicamentos Herbarios Chinos/farmacocinética , Flavonoides/metabolismo , Administración Oral , Animales , Encéfalo/efectos de los fármacos , Citrus/química , Medicamentos Herbarios Chinos/administración & dosificación , Femenino , Flavonoides/sangre , Alcaloides Indólicos/sangre , Ratas Sprague-Dawley , Distribución Tisular , Uncaria/químicaRESUMEN
This data article contains the data on metabolic profiling of healthy human subjects' plasma before and after administration of the Japanese Kampo medicine maoto. Four healthy human subjects were recruited. Plasma samples were collected before and 0.25, 0.5, 1, 2, 4 and 8â¯h after maoto treatment. Endogenous and exogenous compounds in plasma were analyzed using MS. Endogenous compounds including saccharides, amino acids, organic acids and other hydrophilic metabolites were semi-quantitatively measured using GC-MS/MS. Lipid mediators such as arachidonic acid, docosahexaenoic acid and eicosapentaenoic acid were semi-quantitatively measured using LC-MS/MS. Maoto constituents in plasma were quantitatively measured using LC-MS/MS. The data files contain the area ratio values, which were normalized to the intensity of the internal standard, and plasma concentration of maoto compounds. The data article is related to the research article titled "Phenotyping analysis of the Japanese Kampo medicine maoto in healthy human subjects using wide-targeted plasma metabolomics" (Kitagawa et al., 2018).
RESUMEN
Traditional herbal medicine (THM) consists of a vast number of compounds that exert pharmacological effects throughout the body. Comprehensive phenotyping analysis using omics is essential for understanding the nature of THM in detail. We previously reported that the Japanese Kampo medicine maoto ameliorated flu-like symptoms in a rat infection model and dynamically changed plasma metabolites as indicated by metabolome analysis. The aim of this study was to apply wide-targeted plasma metabolomics with quantitative analysis of maoto compounds in a human clinical trial to evaluate the effect of maoto on plasma metabolites. Four healthy human subjects were recruited. Plasma samples were collected before and 0.25, 0.5, 1, 2, 4 and 8 h after maoto treatment. Wide-targeted metabolomics and quantitative analysis of the main chemical constituents of maoto were then performed. Plasma metabolome analysis revealed that maoto administration decreased essential amino acids including branched-chain amino acids (BCAAs) and increased various kinds of ω-3 fatty acids including eicosapentaenoic acid and docosahexaenoic acid, consistent with previous studies in rats. Fifteen of the major compounds in maoto were identified in the systemic circulation. Finally, the correlation between endogenous metabolites and maoto compounds in plasma was analyzed and the results indicated that the decrease in plasma BCAAs might be caused by ephedrines present in maoto. The present study demonstrated that plasma metabolomic studies of endogenous and exogenous metabolites are useful for elucidating the mechanism of action of THM.
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Aminoácidos de Cadena Ramificada/metabolismo , Medicamentos Herbarios Chinos/farmacología , Ácidos Grasos Omega-3/metabolismo , Medicina Kampo/métodos , Metabolómica/métodos , Adulto , Aminoácidos de Cadena Ramificada/sangre , Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/metabolismo , Ácidos Grasos Omega-3/sangre , Voluntarios Sanos , Humanos , Masculino , Metaboloma , Metabolómica/instrumentaciónRESUMEN
Recently, the use of herbal medicines has become popular, and information on drug interactions between herbal medicines and chemical drugs is needed in clinics. In Japan, the number of patients taking Japanese traditional Kampo medicines has been increasing, and the proper drug information about herb-drug interaction is highly demanded. The most established herb-drug interaction is the case of grapefruit juice (GFJ) via the inhibition on CYP3A4 expressed in the small intestine. In the present study, we compared the inhibitory titer on CYP3A4 between the target Kampo products and GFJ used as positive control. We evaluated the inhibitory effects of GFJ and three extracts of Kampo formulas frequently used in gynecological clinics on CYP3A4 in vitro and calculated the related titer of one-time dosage of Kampo formulas to GFJ in order to predict its effect on clinics. Although the extracts of these three Kampo formulas and the most of crude drug components in the formulas exhibited the inhibitory effects on CYP3A4 in some levels, the possibilities of tokishakuyakusan and keishibukuryogan to cause drug interaction can be quite low; however, it is possible that the excessive dosage of kamishoyosan may cause drug interaction with the substrate of CYP3A4 in clinics.
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In modern medical care in which Kampo and Western drugs are often combined, it is extremely important to clarify drug-drug interaction (DDI) to ensure safety and efficacy. However, there is little evidence of DDI in Kampo medicines. Therefore, as part of our studies to clarify the DDI risk for Kampo medicines, we evaluated the effects of five Kampo medicines [yokukansan (YKS), rikkunshito (RKT), shakuyakukanzoto (SKT), hangeshashinto (HST), and goshajinkigan (GJG)] that are widely used in Japan, on drug transporter P-glycoprotein (P-gp) using a Caco-2 permeability assay. These Kampo medicines inhibited the P-gp transport of digoxin through a Caco-2 cell monolayer. The IC50 values were 1.94-10.80 mg/ml. Of the five Kampo medicines, YKS showed the strongest inhibition (IC50 = 1.94 mg/ml), which was attributed to Uncariae Uncis Cum Ramulus. Unfortunately, we could not find the active ingredients responsible for its action. Finally, the Igut/IC50 values for the five Kampo medicines were calculated, and the DDI risk was objectively evaluated according to the criteria in the DDI guidance issued by the Japanese Ministry of Health, Labor, and Welfare and the US Food and Drug Administration. The Igut/IC50 values for the five Kampo medicines were ≤3.4. As these values were <10, they were evaluated as having a weak P-gp inhibitory effect that does not require further verification in humans, suggesting that the DDI risk due to P-gp inhibition for these Kampo medicines is low. The results should provide useful clinical information on the safety and efficacy of the combined use of Kampo and Western medicines.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/efectos de los fármacos , Transporte Biológico/efectos de los fármacos , Células CACO-2/metabolismo , Medicina Kampo/métodos , Interacciones Farmacológicas , Humanos , PermeabilidadRESUMEN
Several basic pharmacokinetic and pharmacological studies were conducted as part of a group of studies to clarify the drug-drug interaction (DDI) between memantine (MEM), a drug used to treat Alzheimer's disease, and yokukansan (YKS), a traditional Japanese Kampo medicine used to treat behavioral and psychological symptoms of dementia. The pharmacokinetic studies showed that there were no statistically significant differences in MEM concentrations in the plasma, brain, and urine between mice treated with MEM alone and with MEM plus YKS. Regarding candidate active ingredients of YKS, there were also no statistically significant differences in concentrations of geissoschizine methyl ether in the plasma and brain, urine, glycyrrhetinic acid in the plasma, and isoliquiritigenin in the urine, in mice treated with YKS alone or with MEM plus YKS. The pharmacological studies showed that isoliquiritigenin, which has an N-methyl-d-aspartic acid (NMDA) receptor antagonistic effect, did not affect the inhibitory effect of MEM on NMDA-induced intracellular Ca2+ influx in primary cultured rat cortical neurons. Moreover, YKS did not affect either the ameliorative effects of MEM on NMDA-induced learning and memory impairment, or the MEM-induced decrease in locomotor activities in mice. These results suggest that there is probably no pharmacokinetic or pharmacological interaction between MEM and YKS in mice, but more detailed studies are needed in the future. Our findings provide important information for future studies, to clarify the DDI more regarding the efficacy and safety of combined use of these drugs in a clinical situation.
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Medicamentos Herbarios Chinos/farmacología , Interacciones de Hierba-Droga , Memantina/farmacología , Animales , Calcio/metabolismo , Medicamentos Herbarios Chinos/farmacocinética , Femenino , Espacio Intracelular/metabolismo , Aprendizaje/efectos de los fármacos , Medicina Kampo , Memantina/farmacocinética , Memoria/efectos de los fármacos , Ratones , Actividad Motora/efectos de los fármacos , Ratas , Receptores de N-Metil-D-Aspartato , Distribución TisularRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The use of herbal medicines has become popular worldwide, and the information on drug interactions between herbal medicines and chemical drugs is needed. AIM OF THE STUDY: We screened the inhibitory effects of crude drugs used in Kampo medicines used in Japan on organic anion-transporting polypeptide (OATP) 2B1 to predict potential interactions between Kampo medicines and chemical drugs used together. MATERIALS AND METHODS: We chose 98 kinds of crude drugs frequently used as ingredients of Kampo formulations in Japan and prepared their boiling water extracts. We then screened their inhibitory effects on OATP2B1 by measuring the uptake of estrone 3-sulphate (E3S) by HEK293 cells stably expressing OATP2B1. RESULTS: At the concentration of 100µg/ml, the extracts prepared from 12 kinds of crude drugs, Scuteralliae Radix, Arecae Semen, Aurantii Fructus Immaturus, Perillae Herba, Panacis Japonici Rhizoma, Moutan Cortex, Polygalae Radix, Rhei Rhizoma, Cannabis Fructus, Chrysanthemi Flos, Eriobotryae Folium, and Querci Cortex, suppressed the function of OATP2B1 by less than 20%. The extract of bofutsushosan, a representative Kampo formulation, inhibited OATP2B1 function with sufficient levels to suppress absorption of OATP2B1 substrates in clinics. We further evaluated the inhibitory effects of several ingredients containing Rhei Rhizoma, Perillae Herba, and Moutan Cortex on OATP2B1. CONCLUSIONS: Because of crude drugs used in Kampo medicines might suppress absorption of OATP2B1 substrates, these results may contribute to the safe and effective use of Kampo medicine in clinics. A list of abbreviations: EC, (-)-epicatechin; ECG, epicatechin gallate; EGC, epigallocatechin; EGCG, Epigallocatechin gallate; FBS, fetal bovine serum; grapefruit juice; HEK293, Human embryonic kidney; IC50, The half inhibitory concentration; OATP, organic anion-transporting polypeptide; ß-PGG, penta-O-galloyl-ß-D-glucose; t.i.d, 3 times a day.
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Interacciones de Hierba-Droga , Medicina Kampo , Transportadores de Anión Orgánico/antagonistas & inhibidores , Extractos Vegetales/farmacología , Relación Dosis-Respuesta a Droga , Estrona/análogos & derivados , Estrona/metabolismo , Células HEK293 , Humanos , Transportadores de Anión Orgánico/genética , Transportadores de Anión Orgánico/metabolismo , Fitoterapia , Extractos Vegetales/toxicidad , Plantas Medicinales , Medición de Riesgo , TransfecciónRESUMEN
Herbal medicines and natural products used for maintenance of health or treatment of diseases have many biological effects, including altering the pharmacokinetics and metabolism of other medications. Daikenchuto (TU-100), an aqueous extract of ginger, ginseng, and Japanese green pepper fruit, is a commonly prescribed Kampo (Japanese herbal medicine) for postoperative ileus or bloating. The effects of TU-100 on drug metabolism have not been investigated. In this study, we analyzed the effect of TU-100 on expression of key drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in murine liver and gastrointestinal tract using a dietary model. Liver, jejunum, and proximal colon were analyzed for phase I and II DMEs and DT mRNA expression by reverse transcription (RT) first by nonquantitative and followed by quantitative polymerase chain reaction (PCR) and protein expression. Liver, jejunum, and proximal colon expressed some identical but also unique DMEs and DTs. TU-100 increased the greatest changes in cytochrome (Cyp) 2b10 and Cyp3a11 and Mdr1a. Basal and TU-100 stimulated levels of DME and DT expression were gender-dependent, dose-dependent and reversible after cessation of TU-100 supplementation, except for some changes in the intestine. Quantitative Western blot analysis of protein extracts confirmed the quantitative PCR results.
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Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Hidrocarburo de Aril Hidroxilasas/genética , Citocromo P-450 CYP3A/genética , Familia 2 del Citocromo P450/genética , Intestinos/enzimología , Hígado/enzimología , Proteínas de la Membrana/genética , Extractos Vegetales/efectos adversos , Esteroide Hidroxilasas/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Animales , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP3A/metabolismo , Familia 2 del Citocromo P450/metabolismo , Suplementos Dietéticos/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Intestinos/efectos de los fármacos , Hígado/efectos de los fármacos , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Modelos Animales , Panax , Factores Sexuales , Esteroide Hidroxilasas/metabolismo , Zanthoxylum , ZingiberaceaeRESUMEN
Maoto, a traditional Japanese Kampo medicine, has been used to treat various respiratory diseases, including respiratory infections and influenza. Ephedrine (EPD), the main ingredient in maoto, is also clinically used to treat respiratory diseases. However, the pharmacokinetics and distribution of EPD in the lungs after the administration of maoto have not been demonstrated. This study aimed to determine the concentrations, distribution, and pharmacokinetics of EPD and its precursor methylephedrine (MEPD) in the lungs of rats orally administered maoto (1 and 4 g/kg). We used liquid chromatography-electrospray ionization-tandem mass spectrometry to measure the ingredient concentrations. Both ingredients were detected in maoto-treated lung homogenates. Next, we examined the distribution of both ingredients in lung sections by using matrix-assisted laser desorption/ionization-mass spectrometry imaging, a powerful tool for the visualization of the distribution of biological molecules. The mass spectrometry imaging analysis detected only EPD and provided the first visual demonstration that EPD is distributed in the alveoli, bronchi, and bronchioles in the lungs of rats orally administered maoto (4 g/kg, three times at 2-h intervals). These results suggest that the pharmacological efficacy of maoto for the amelioration of respiratory symptoms is related to the distribution of EPD in the lung.
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Efedrina/análogos & derivados , Efedrina/análisis , Efedrina/farmacología , Pulmón/química , Medicina Kampo , Administración Oral , Animales , Efedrina/química , Japón , Pulmón/efectos de los fármacos , Masculino , Espectrometría de Masas , Extractos Vegetales/química , Ratas Sprague-DawleyRESUMEN
Many pharmaceutical agents not only require microbial metabolism for increased bioavailability and bioactivity, but also have direct effects on gut microbial assemblage and function. We examined the possibility that these actions are not mutually exclusive and may be mutually reinforcing in ways that enhance long-term of these agents. Daikenchuto, TU-100, is a traditional Japanese medicine containing ginseng. Conversion of the ginsenoside Rb1 (Rb1) to bioactive compound K (CK) requires bacterial metabolism. Diet-incorporated TU-100 was administered to mice over a period of several weeks. T-RFLP and 454 pyrosequencing were performed to analyze the time-dependent effects on fecal microbial membership. Fecal microbial capacity to metabolize Rb1 to CK was measured by adding TU-100 or ginseng to stool samples to assess the generation of bioactive metabolites. Levels of metabolized TU-100 components in plasma and in stool samples were measured by LC-MS/MS. Cecal and stool short-chain fatty acids were measured by GC-MS. Dietary administration of TU-100 for 28 days altered the gut microbiota, increasing several bacteria genera including members of Clostridia and Lactococcus lactis. Progressive capacity of microbiota to convert Rb1 to CK was observed over the 28 days administration of dietary TU-100. Concomitantly with these changes, increases in all SCFA were observed in cecal contents and in acetate and butyrate content of the stool. Chronic consumption of dietary TU-100 promotes changes in gut microbiota enhancing metabolic capacity of TU-100 and increased bioavailability. We believe these findings have broad implications in optimizing the efficacy of natural compounds that depend on microbial bioconversion in general.
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1. Yokukansan (YKS) is a traditional Japanese medicine also called kampo, which has been used to treat neurosis, insomnia, and night crying and peevishness in children. Geissoschizine methyl ether (GM), a major indole alkaloid found in Uncaria hook, has been identified as a major active component of YKS with psychotropic effects. Recently, GM was reported to have a partial agonistic effect on serotonin 5-HT1A receptors. However, there is little published information on GM metabolism in humans, although several studies reported the blood kinetics of GM in rats and humans. In this study, we investigated the GM metabolic pathways and metabolizing enzymes in humans. 2. Using recombinant human cytochrome P450 (CYP) isoforms and polyclonal antibodies to CYP isoforms, we found that GM was metabolized into hydroxylated, dehydrogenated, hydroxylated+dehydrogenated, demethylated and water adduct forms by some CYP isoforms. 3. The relative activity factors in human liver microsomes were calculated to determine the relative contributions of individual CYP isoforms to GM metabolism in human liver microsomes (HLMs). We identified CYP3A4 as the CYP isoform primarily responsible for GM metabolism in human liver microsomes. 4. These findings provide an important basis for understanding the pharmacokinetics and pharmacodynamics of GM and YKS.
Asunto(s)
Sistema Enzimático del Citocromo P-450/metabolismo , Medicamentos Herbarios Chinos/química , Alcaloides Indólicos/metabolismo , Cromatografía Liquida , Femenino , Humanos , Alcaloides Indólicos/química , Isoenzimas/metabolismo , Masculino , Redes y Vías Metabólicas , Metaboloma , Microsomas Hepáticos/metabolismo , Proteínas Recombinantes/metabolismo , Especificidad por Sustrato , Espectrometría de Masas en TándemRESUMEN
A pharmaceutical grade Japanese traditional medicine, daikenchuto (TU-100), consisting of Japanese pepper, processed ginger, and ginseng, has been widely used for various intestinal disorders in Japan and now under development as a new therapeutic drug in the US. It is suggested that TU-100 ingredients exert pharmacological effects on intestines via two routes, from the luminal side before absorption and the peripheral blood stream after absorption. Therefore, in order to fully understand the pharmacological actions of TU-100, it is critically important to know the intraluminal amounts and forms of ingested TU-100 ingredients. In the present study, after administrating TU-100 to rats, the concentrations of TU-100 ingredients and their conjugates in the peripheral and portal blood and ileal contents were determined by LC-MS/MS. Next, TU-100 was administered to patients with ileostomy bags, but whose small intestines are diagnosed as healthy, and the ingredients/conjugates in the ileal effluent were analyzed. The results suggest that: (1) Pepper ingredients hydroxysanshools are rapidly absorbed and enter systemic circulation, (2) Ginseng ingredients ginsenosides are transported to the colon with the least absorption, (3) Ginger ingredients gingerols are absorbed and some conjugated in the small intestine and transported via the portal vein. While only a small amount of gingerols/gingerol conjugates enter systemic circulation, considerable amounts reappear in the small intestine. Thus, the effect of TU-100 on the intestines is believed to be a composite of multiple actions by multiple compounds supplied via multiple routes.
RESUMEN
Most orally administered polyphenols are metabolized, with very little absorbed as aglycones and/or unchanged forms. Metabolic and pharmacokinetic studies are therefore necessary to understand the pharmacological mechanisms of polyphenols. Jumihaidokuto (JHT), a traditional Japanese medicine, has been used for treatment of skin diseases including inflammatory acne. Because JHT contains various types of bioactive polyphenols, our aim was to clarify the metabolism and pharmacokinetics of the polyphenols in JHT and identify active metabolites contributing to its antidermatitis effects. Orally administered JHT inhibited the increase in ear thickness in rats induced by intradermal injection of Propionibacterium acnes. Quantification by LC-MS/MS indicated that JHT contains various types of flavonoids and is also rich in hydrolysable tannins, such as 1,2,3,4,6-penta-O-galloyl glucose. Pharmacokinetic and antioxidant analyses showed that some flavonoid conjugates, such as genistein 7-O-glucuronide and liquiritigenin 7-O-glucuronide, appeared in rat plasma and had an activity to inhibit hydrogen peroxide-dependent oxidation. Furthermore, 4-O-methylgallic acid, a metabolite of Gallic acid, appeared in rat plasma and inhibited the nitric oxide reaction. JHT has numerous polyphenols; it inhibited dermatitis probably via the antioxidant effect of its metabolites. Our study is beneficial for understanding in vivo actions of orally administered polyphenol drugs.
Asunto(s)
Antiinflamatorios/farmacocinética , Antioxidantes/farmacocinética , Dermatitis/tratamiento farmacológico , Extractos Vegetales/farmacocinética , Polifenoles/farmacocinética , Propionibacterium acnes/inmunología , Administración Oral , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/sangre , Antioxidantes/administración & dosificación , Dermatitis/microbiología , Flavanonas/sangre , Flavanonas/farmacocinética , Genisteína/sangre , Genisteína/farmacocinética , Masculino , Medicina Tradicional , Extractos Vegetales/administración & dosificación , Extractos Vegetales/sangre , Polifenoles/administración & dosificación , Polifenoles/sangre , Ratas , Ratas Sprague-DawleyRESUMEN
Purpose. Macrophages serve as sweepers of microbes and inflammation-derived wastes and regulators of inflammation. Some traditional Japanese medicines are reported to have adjuvant effects by modifying macrophages. Our aim was to characterize the actions of jumihaidokuto (JHT) for treatment of skin inflammations including acne vulgaris, in which Propionibacterium acnes has pathogenic roles. Methods. Dermatitis was induced in rat ears by intradermal injection of P. acnes. JHT or prednisolone (PDN) was given orally, and ear thickness and histology were evaluated. The effects of constituents and metabolites of JHT on monocytes were tested by cell-based assays using the human monocytic THP-1 cell. Results. JHT and PDN suppressed the ear thickness induced by P. acnes injection. Histological examinations revealed that JHT, but not PDN, promoted macrophage accumulation at 24 h after the injection. PDN suppressed the macrophage chemokine MCP-1 in the inflamed ears, while JHT did not affect it. The JHT constituents liquiritigenin and isoliquiritin increased expression of CD86 (type-1 macrophage marker) and CD192 (MCP-1 receptor) and enhanced phagocytosis by THP-1. Conclusions. JHT suppressed dermatitis, probably by enhancing type-1 macrophage functions, with an action different from PDN. JHT may be a beneficial drug in treatment of skin inflammation induced by P. acnes.