Intestinal, portal, and peripheral profiles of daikenchuto (TU-100)'s active ingredients after oral administration.

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.

Pharmacokinetic Profiles of Active Components After Oral Administration of a Kampo Medicine, Shakuyakukanzoto, to Healthy Adult Japanese Volunteers.

Shakuyakukanzoto (SKT), a traditional Japanese (Kampo) medicine, has been used by patients with muscle cramps and abdominal pains. In this trial, we analyzed plasma concentrations of active components after SKT was administered as a single oral dose of 2.5 or 5.0 g/day per person. The study was a randomized, open-label, two-arm, two-period, crossover trial conducted in healthy Japanese volunteers. Albiflorin (ALB), paeoniflorin (PAE), glycycoumarin (GCM), isoliquiritigenin (ILG), glycyrrhetic acid (GA), and glycyrrhetic acid-3-O-monoglucuronide were targeted, and the plasma concentration of each component was measured using a liquid chromatography-tandem mass spectrometry method. The pharmacokinetic parameters were calculated, and the linearity was assessed. All targeted components were detected in the plasma after oral administration of SKT. ALB, PAE, GCM, and ILG were detected at an early stage. The linearity was observed for the maximum plasma concentration of GCM, ILG, and GA and for the area under the plasma concentration-time curve of GA. In this trial, we demonstrated for the first time in humans that these components were absorbed into the blood after oral administration of SKT. The results of this pharmacokinetic trial in humans are also important and useful for understanding the mechanism of action of SKT, verifying the active components predicted in basic research, and conducting pharmacokinetics and safety studies in the future.

Pharmacokinetic Profiles of Active Ingredients and Its Metabolites Derived from Rikkunshito, a Ghrelin Enhancer, in Healthy Japanese Volunteers: A Cross-Over, Randomized Study.

BACKGROUND: Rikkunshito, a traditional Japanese (Kampo) medicine, has been used to treat upper gastrointestinal disorders such as functional dyspepsia and gastroesophageal reflux. This study investigated the exposure and pharmacokinetics of the ingredients of rikkunshito in healthy volunteers. METHODS AND RESULTS: First, an exploratory nonrandomized, open-label, one-period, noncrossover study using four healthy Japanese volunteers to detect 32 typical ingredients of rikkunshito in plasma and urine. As a result, 18 or 21 of 32 ingredients was detected in plasma or urine samples after oral administration of rikkunshito (7.5 g/day). Furthermore, a randomized, open-label, three-arm, three-period, crossover study using 21 subjects was conducted to determine the amounts of exposure and pharmacokinetic parameters of nine ingredients derived from rikkunshito (atractylodin, atractylodin carboxylic acid, pachymic acid, 3,3',4',5,6,7,8-heptamethoxyflavone, naringenin, nobiletin, liquiritigenin, isoliquiritigenin, and 18ß-glycyrrhetinic acid) after oral administration of rikkunshito at three different doses (2.5, 5.0, or 7.5 g/day) during each period. The pharmacokinetic profiles of the nine ingredients in plasma were characterized. The geometric means (95% confidence interval) for the Cmax of the ingredients at a dose of 7.5 g were 1570 (1210-2040), 14,300 (12,200-16,800), 91.0 (71.8-115), 105 (75.6-144), 1150 (802-1650), 35.9 (24.6-52.5), 800 (672-952), 42.8 (30.4-60.3), and 55,600 (39,600-78,100) pg/mL, respectively, and for the AUC0-last were 1760 (1290-2390), 12700 (11,100-14,600), 1210 (882-1650), 225 (157-322), 4630 (2930-7320), 35.7 (20.4-62.7), 4040 (3260-5010), 122 (88.2-168), and 832,000 (628,000-1,100,000) pg·h/mL respectively. CONCLUSIONS: We identified the ingredients of rikkunshito that are absorbed in humans. Furthermore, we determined the pharmacokinetics of nine ingredients derived from rikkunshito. This information will be useful for elucidating the pharmacological effects of rikkunshito. TRIAL REGISTRATION: Japan Pharmaceutical Information Center #CTI-121801 and -142522.

Effects of shakuyakukanzoto and its absorbed components on twitch contractions induced by physiological Ca2+ release in rat skeletal muscle.

Shakuyakukanzoto (SKT) is a kampo medicine composed of equal proportions of Glycyrrhizae radix (G. radix) and Paeoniae radix (P. radix). A double-blind study reported that SKT significantly ameliorated painful muscle cramp in cirrhosis patients without the typical severe side effects of muscle weakness and central nervous system (CNS) depression. Previous basic studies reported that SKT and its active components induced relaxation by a direct action on skeletal muscle and that SKT did not depress CNS functions; however, why SKT has a lower incidence of muscle weakness remains unknown. In the present study, we investigated which components are absorbed into the blood of rats after a single oral administration of SKT to identify the active components of SKT. We also investigated the effects of SKT and its components on the twitch contraction induced by physiological Ca(2+) release. Our study demonstrated that SKT and five G. radix isolates, which are responsible for the antispasmodic effect of SKT, did not inhibit the twitch contraction in contrast to dantrolene sodium, a direct-acting peripheral muscle relaxant, indicating that the mechanisms of muscle contraction of SKT and dantrolene in skeletal muscle differ. These findings suggest that SKT does not reduce the contractile force in skeletal muscle under physiological conditions, i.e., SKT may have a low risk of causing muscle weakness in clinical use. Considering that most muscle relaxants and anticonvulsants cause various harmful side effects such as weakness and CNS depression, SKT appears to have a benign safety profile.

Simultaneous quantitative analyses of indole and oxindole alkaloids of Uncaria Hook in rat plasma and brain after oral administration of the traditional Japanese medicine Yokukansan using high-performance liquid chromatography with tandem mass spectrometry.

Uncaria Hook (UH) alkaloids are involved in the beneficial effects of Yokukansan. However, the pharmacokinetics of UH alkaloids after oral administration of Yokukansan has not yet been sufficiently investigated. Therefore, we developed and validated a sensitive and specific high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantitation of seven UH alkaloids (corynoxeine, isocorynoxeine, rhynchophylline, isorhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether) in rat plasma and brain. After protein precipitation with acetonitrile, chromatographic separation was performed using an Ascentis Express RP-amide column, with gradient elution with 0.2% formic acid and acetonitrile at 0.3 mL/min. All analytes in the plasma and brain showed good linearity over a wide concentration range (r > 0.995). Intra-day and inter-day variations of each constituent were 8.6 and 8.0% or less in the plasma, and 14.9 and 15.0% or less in the brain, respectively. The validated LC/MS/MS method was applied in the pharmacokinetic studies of UH alkaloids after oral administration of Yokukansan to rats. In the plasma, rhynchophylline, hirsutine, hirsuteine and geissoschizine methyl ether were detected, but only geissoschizine methyl ether was detected in the brain. These results suggest that geissoschizine methyl ether is an important constituent of the pharmacological effects of Yokukansan.