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

Abstract

ContextYokukansan (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.ObjectiveTo confirm the exposure and pharmacokinetics of the active components of YKS in healthy volunteers.Design, Setting, and ParticipantsA 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.InterventionsSingle oral administration of YKS (2.5 g, 5.0 g, or 7.5 g/day) during each period.Main Outcome MeasurePlasma concentrations of three active compounds in YKS, namely 18β-glycyrrhetinic acid (GA), geissoschizine methyl ether (GM), and hirsuteine (HTE).ResultsThe mean maximum plasma concentrations (Cmax) 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.ConclusionWe 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.Trial RegistrationJapan Pharmaceutical Information Center JAPIC CTI-121811

Effect of maternal yokukansan treatment on somatosensory map formation in the cerebral cortex of newborn mouse pups

“…In this study, we used the somatosensory system of mice to examine the possible adverse effects of yokukansan. The pharmacokinetics of the active components of yokukansan, such as geissoschizine methyl ether (GM), hirsuteine and 18β‐glycyrrhetinic acid (GA) have been investigated in healthy Japanese volunteers . It was found that the plasma GA concentration was high compared with that of GM and of hirsuteine because GM and hirsuteine are rapidly eliminated, with half‐lives of approximately 2 h, whereas the half‐life of GA was approximately 10 h .…”

“…The pharmacokinetics of the active components of yokukansan, such as geissoschizine methyl ether (GM), hirsuteine and 18β‐glycyrrhetinic acid (GA) have been investigated in healthy Japanese volunteers . It was found that the plasma GA concentration was high compared with that of GM and of hirsuteine because GM and hirsuteine are rapidly eliminated, with half‐lives of approximately 2 h, whereas the half‐life of GA was approximately 10 h . Interestingly, the plasma GM and hirsuteine concentrations were almost identical between mice and humans .…”

“…It was found that the plasma GA concentration was high compared with that of GM and of hirsuteine because GM and hirsuteine are rapidly eliminated, with half‐lives of approximately 2 h, whereas the half‐life of GA was approximately 10 h . Interestingly, the plasma GM and hirsuteine concentrations were almost identical between mice and humans . Therefore, it seems reasonable to use mice to examine the effects of yokukansan.…”

Yokukansan enhances the proliferation of B65 neuroblastoma

“…In addition, yokukansan has the potential to increase hippocampal neurogenesis associated with the suppression of activated microglia 22 . Furthermore, several studies related to pharmacokinetics of yokukansan have demonstrated that several compounds contained to yokukansan migrate to both plasma and brain after oral administration in in vivo experiments 23, 24. According to these studies, it is reasonable to consider that yokukansan and its compounds would distribute to the brain by oral administration and be effective for the treatment of depression or anxiety disorder and the mechanism may be similar to those of antidepressants.…”

The Effect of <i>Yokukansan</i>, a Traditional Herbal Preparation Used for the Behavioral and Psychological Symptoms of Dementia, on the Drug–Metabolizing Enzyme Activities in Healthy Male Volunteers

“…We were therefore unable to compare the dose of the ingredients in YKS used in the present study with that in the previous in vitro studies. In one clinical study, the pharmacokinetic parameters of several active ingredients of YKS, such as 18β-glycyrrhetinic acid and geissoschizine methyl ether, were determined in healthy subjects, 36) but there are presently no data available regarding the blood concentrations of the ingredients listed in Supplementary Table 1. In addition, we were unable to collect enough blood samples to assess the concentration of each ingredient of these herbal components.…”