ラットにおけるグリチルレチン酸の吸収に及ぼすセンノサイド類の影響

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第1745号 , 学位授与年月日 : 平成18年3月22日, 学位授与大学 : 金沢大

Use of a Caco-2 permeability assay to evaluate the effects of several Kampo medicines on the drug transporter P-glycoprotein

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

Pharmacokinetics of (-)Epicatechin 3-O-Gallate, Glycyrrhetic Acid and Rhein in Healthy Male Volunteers after a Single Dose Administration of TJ-8117 (Unpito), a Japanese Traditional Medicine for Renal Failure

Aims: Unpito, an herbal medicine extracted from a mixture of five crude medicines (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), has been developed as a drug for chronic renal failure. In general, it is difficult to estimate the absorption and excretion of herbal medicines due to the presence of a wide variety of components. The purpose of the current study was to examine the systemic pharmacokinetics and elimination of Unpito in healthy volunteers as part of the clinical study of the medicine. Methods: Three compounds, (-)epicatechin 3-O-gallate (ECG), glycyrrhetic acid (GA) and rhein (RH) were selected as markers, to examine the clinical pharmacokinetics of Unpito based on their levels in this medicine. The disposition of each compound was evaluated in 32 healthy volunteers receiving single oral doses (2, 4, 8, and 12 capsules). Results: After a single oral administration, ECG and RH exhibited linear pharmacokinetics in AUC and C max, while GA did not exhibit linear pharmacokinetics. A cross-over study was conducted to evaluate the effect of food at a single dose of 4 capsules. The effect of food was observed for the plasma concentrations of ECG and RH, while not for GA. The potential accumulations of δ-(3,4- dihydroxyphenyl)-γ-valerolactone (VL-2), a metabolite of ECG and RH were not observed. GA was not detected in urine. Conclusions: This is the first study presenting pharmacokinetics of ECG, GA and RH derived from Unpito, an herbal medicine, in healthy volunteers after single dose administration.出版者照会後に全文公

CRF receptor 1 antagonism and brain distribution of active components contribute to the ameliorative effect of rikkunshito on stress-induced anorexia

Rikkunshito (RKT), a Kampo medicine, has been reported to show an ameliorative effect on sustained hypophagia after novelty stress exposure in aged mice through serotonin 2C receptor (5-HT2CR) antagonism. We aimed to determine (1) whether the activation of anorexigenic neurons, corticotropin-releasing factor (CRF), and pro-opiomelanocortin (POMC) neurons, is involved in the initiation of hypophagia induced by novelty stress in aged mice; (2) whether the ameliorative effect of RKT is associated with CRF and POMC neurons and downstream signal transduction; and (3) the plasma and brain distribution of the active components of RKT. The administration of RKT or 5-HT2CR, CRF receptor 1 (CRFR1), and melanocortin-4 receptor antagonists significantly restored the decreased food intake observed in aged male C57BL/6 mice in the early stage after novelty stress exposure. Seven components of RKT exhibited antagonistic activity against CRFR1. Hesperetin and isoliquiritigenin, which showed antagonistic effects against both CRFR1 and 5-HT2CR, were distributed in the plasma and brain of male Sprague-Dawley rats after a single oral administration of RKT. In conclusion, the ameliorative effect of RKT in this model is assumed to be at least partly due to brain-distributed active components possessing 5-HT2CR and CRFR1 antagonistic activities

Pharmacokinetics of (-)Epicatechin 3-O-Gallate, Glycyrrhetic Acid and Rhein in Healthy Male Volunteers after Multiple Dose Administration of TJ-8117 (Unipito), a Japanese Traditional Medicine for Renal Failure

Aims: Unpito, an herbal medicine extracted from a mixture of five crude medicines (Rhei Rhizoma, Glycyrrhizae Radix, Ginseng Radix, Zingiberis Rhizoma and Aconiti Tuber), has been developed as a drug for chronic renal failure. In general, it is difficult to estimate the absorption and excretion of herbal medicines due to the presence of a wide variety of components. The purpose of the current study was to examine the systemic pharmacokinetics and elimination of Unpito in healthy volunteers following repeated administration as part of the clinical study of the medicine. Methods: Three compounds, (-) epicatechin 3-O-gallate (ECG), glycyrrhetic acid (GA) and rhein (RH) were selected as markers, to examine the clinical pharmacokinetics of Unpito based on their levels in this medicine. The disposition of each compound was evaluated in 24 healthy volunteers receiving multiple oral doses (4, 6, and 8 capsules three times a day). Results: After repeated administration, plasma ECG and GA concentrations were lower than those simulated. RH plasma concentrations were consistent with the simulation, indicating linear pharmacokinetics of RH. The potential accumulations of marker compounds were not observed from the roughly constant plasma concentrations of troughs at 72, 120, and 144 h after the first administration nor from the urinary excretions. Conclusions: This is the first study presenting pharmacokinetics of ECG, GA and RH derived from Unpito, an herbal medicine, in healthy volunteers after multiple dose administration