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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.

Kitagawa H, Munekage M, Ichikawa K, Fukudome I, Munekage E, Takezaki Y, Matsumoto T, Igarashi Y, Hanyu H, Hanazaki K - PLoS ONE (2015)

Bottom Line: Further, we determined the pharmacokinetics of GM, HTE, and GA.This information will be useful to elucidate the pharmacological effects of YKS.Japan Pharmaceutical Information Center JAPIC CTI-121811.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan.

ABSTRACT

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 18β-glycyrrhetinic acid (GA), geissoschizine methyl ether (GM), and hirsuteine (HTE).

Results: The 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 (tmax) were 0.500 h for GM and 0.975-1.00 h for HTE. The apparent elimination half-lives (t1/2) 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 Cmax, tmax, and t1/2 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.

Trial registration: Japan Pharmaceutical Information Center JAPIC CTI-121811.

No MeSH data available.


Related in: MedlinePlus

Relations between log-transformed dosage and Cmax or AUC0–last.A; geissoschizine methyl ether, B; hirsuteine, and C; 18β-glycyrrhetinic acid. Power regression model was fitted to the mixed effect model for evaluation of linearity. CI; confidence interval.
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pone.0131165.g004: Relations between log-transformed dosage and Cmax or AUC0–last.A; geissoschizine methyl ether, B; hirsuteine, and C; 18β-glycyrrhetinic acid. Power regression model was fitted to the mixed effect model for evaluation of linearity. CI; confidence interval.

Mentions: The dose proportionality of Cmax and AUC0–last are displayed in Fig 4. The estimated β (90% confidence interval) of Cmax for GM was 1.02 (0.827–1.21), and the 90% confidence intervals included 1 for doses ranging between 2.5 and 7.5 g of YKS. These results suggested that the Cmax of GM was linear within the dose range of 2.5 to 7.5 g/day of YKS. However, the 90% confidence intervals of the β value of HTE and GA for Cmax and GM, HTE, and GA for AUC0–last did not include 1, and confidence limits were out of the range of 0.8–1.25. The estimate of the covariance parameter showed that the between-subject variability (σa2 = 0.216) was larger than the random error variability (σ2 = 0.0889). This suggested that the crossover design was appropriate.


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.

Kitagawa H, Munekage M, Ichikawa K, Fukudome I, Munekage E, Takezaki Y, Matsumoto T, Igarashi Y, Hanyu H, Hanazaki K - PLoS ONE (2015)

Relations between log-transformed dosage and Cmax or AUC0–last.A; geissoschizine methyl ether, B; hirsuteine, and C; 18β-glycyrrhetinic acid. Power regression model was fitted to the mixed effect model for evaluation of linearity. CI; confidence interval.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495062&req=5

pone.0131165.g004: Relations between log-transformed dosage and Cmax or AUC0–last.A; geissoschizine methyl ether, B; hirsuteine, and C; 18β-glycyrrhetinic acid. Power regression model was fitted to the mixed effect model for evaluation of linearity. CI; confidence interval.
Mentions: The dose proportionality of Cmax and AUC0–last are displayed in Fig 4. The estimated β (90% confidence interval) of Cmax for GM was 1.02 (0.827–1.21), and the 90% confidence intervals included 1 for doses ranging between 2.5 and 7.5 g of YKS. These results suggested that the Cmax of GM was linear within the dose range of 2.5 to 7.5 g/day of YKS. However, the 90% confidence intervals of the β value of HTE and GA for Cmax and GM, HTE, and GA for AUC0–last did not include 1, and confidence limits were out of the range of 0.8–1.25. The estimate of the covariance parameter showed that the between-subject variability (σa2 = 0.216) was larger than the random error variability (σ2 = 0.0889). This suggested that the crossover design was appropriate.

Bottom Line: Further, we determined the pharmacokinetics of GM, HTE, and GA.This information will be useful to elucidate the pharmacological effects of YKS.Japan Pharmaceutical Information Center JAPIC CTI-121811.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Kochi Medical School, Kochi University, Kochi, Japan.

ABSTRACT

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 18β-glycyrrhetinic acid (GA), geissoschizine methyl ether (GM), and hirsuteine (HTE).

Results: The 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 (tmax) were 0.500 h for GM and 0.975-1.00 h for HTE. The apparent elimination half-lives (t1/2) 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 Cmax, tmax, and t1/2 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.

Trial registration: Japan Pharmaceutical Information Center JAPIC CTI-121811.

No MeSH data available.


Related in: MedlinePlus