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

<div><p>Background</p><p>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.</p><p>Methods and Results</p><p>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 18β-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 AUC_0–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.</p><p>Conclusions</p><p>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.</p><p>Trial Registration</p><p>Japan Pharmaceutical Information Center <a href="http://www.clinicaltrials.jp/user/cteDetail_e.jsp" target="_blank">#CTI-121801 and -142522</a></p></div

Chemical structures of nine ingredients derived from rikkunshito

<p>Chemical structures of nine ingredients derived from rikkunshito</p

Clinical and demographic characteristics of study participants.

<p>BMI; body mass index. Data represent the median (minimum–maximum).</p

Plasma concentrations of nine ingredients derived from rikkunshito A; atractylodin, B; atractylodin carboxylic acid, C; pachymic acid, D; heptamethoxyflavone, E; naringenin, F; nobiletin, G; liquiritigenin, H; isoliquiritigenin, I; 18β-glycyrrhetinic acid.

<p>Blood samples were collected at 0 (beginning of the study), 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, and 48 h after administration of rikkunshito (2.5, 5.0, or 7.5 g/day). Each value represents mean ± S.D. (<i>n</i> = 19–21).</p

Relations between dosage and <i>C</i>_max or AUC_{<i>0–last</i>} A; atractylodin, B; 18β-glycyrrhetinic acid, C, D; atractylodin carboxylic acid.

<p>A power regression model was fitted to a mixed-effect model for evaluation of linearity. CI; confidence interval.</p