Pharmacokinetics of Active Components of Yokukansan, a Traditional Japanese Herbal Medicine after a Single Oral Administration to Healthy Japanese Volunteers: A Cross-Over, Randomized Study

Context Yokukansan (YKS) is a traditional Japanese herbal medicine called kampo medicine in Japan. Its extract comprises seven crude drugs: Atractylodis lanceae rhizoma, Poria, Cnidii rhizoma, Uncariae uncis cum ramulus, Angelicae radix, Bupleuri radix, and Glycyrrhizae radix. YKS is used to treat neurosis, insomnia, as well as behavioral and psychological symptoms of dementia. Objective To confirm the exposure and pharmacokinetics of the active components of YKS in healthy volunteers. Design, Setting, and Participants A randomized, open-label, 3-arm, 3-period, crossover trial was conducted on 21 healthy Japanese volunteers at the Kochi Medical University between May 2012 and November 2012. Interventions Single oral administration of YKS (2.5 g, 5.0 g, or 7.5 g/day) during each period. Main Outcome Measure Plasma concentrations of three active compounds in YKS, namely 18 beta-glycyrrhetinic acid (GA), geissoschizine methyl ether (GM), and hirsuteine (HTE). Results The mean maximum plasma concentrations (C-max) of GM and HTE increased dose-dependently (ranges: 0.650-1.98 ng/mL and 0.138-0.450 ng/mL, respectively). The times to maximum plasma concentration after drug administration (t(max)) were 0.500 h for GM and 0.975-1.00 h for HTE. The apparent elimination half-lives (t(1/2)) were 1.72-1.95 h for GM and 2.47-3.03 h for HTE. These data indicate the rapid absorption and elimination of GM and HTE. On the other hand, the C-max, t(max), and t(1/2) of GA were 57.7-108 ng/mL, 8.00-8.01 h, and 9.39-12.3 h, respectively. Conclusion We demonstrated that pharmacologically active components of YKS are detected in humans. Further, we determined the pharmacokinetics of GM, HTE, and GA. This information will be useful to elucidate the pharmacological effects of YKS.