title: Pharmacokinetic Profiles of Active Ingredients and Its Metabolites Derived from Rikkunshito, a Ghrelin Enhancer, in Healthy Japanese Volunteers: A Cross-Over, Randomized Study.
abstract: 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.
  
  
  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 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 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.
  
  
  BACKGROUND
  Japan Pharmaceutical Information Center #CTI-121801 and -142522.
authors.affiliation: Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitagawa
authors.affiliation: Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Masaya
authors.initials: M
authors.lastname: Munekage
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Sadakane
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan.
authors.forename: Miwako
authors.initials: M
authors.lastname: Fukutake
authors.affiliation: Kampo Formulations Development Center, Production Division, Tsumura & Co., Ibaraki, Japan.
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Aoki
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Watanabe
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Maemura
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Hattori
authors.affiliation: Tsumura Research Laboratories, Kampo Scientific Strategies Division, Tsumura & Co., Ibaraki, Japan.
authors.forename: Yosio
authors.initials: Y
authors.lastname: Kase
authors.affiliation: Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
authors.affiliation: Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Inui
authors.affiliation: Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hanazaki
mesh_terms: D000328:Adult; D047188:Chalcones / Q000032:analysis; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D005419:Flavonoids / Q000032:analysis; D064368:Healthy Volunteers; D006569:Hesperidin / Q000032:analysis; D006801:Humans; D008297:Male; D014315:Triterpenes / Q000032:analysis
chemical_list: D047188:Chalcones; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D014315:Triterpenes; C084136:liu-jun-zi-tang; C040920:isoliquiritigenin; D006569:Hesperidin; C102487:pachymic acid