著者

堀井 周文 小此木 明 高橋 隆二 鎌倉 浩之 袴塚 高志 合田 幸広

出版者

一般社団法人 日本生薬学会

雑誌

生薬学雑誌 (ISSN:13499114)

巻号頁・発行日

vol.74, no.1, pp.46-57, 2020-02-20 (Released:2021-03-11)

参考文献数

29

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Our previous studies [Horii, C., et al., Shoyakugaku Zasshi, 68(1), 9-12 (2014); Shoyakugaku Zasshi, 69(2), 59-65 (2015); Shoyakugaku Zasshi, 68(2), 65-69, (2014); Shoyakugaku Zasshi, 73(2), 73-83 (2019)], in which bioequivalence between the Kakkonto /Shoseiryuto decoction and its extract preparation was evaluated, revealed that some components can be marker compounds for bioequivalence but not others. In this study, we selected Hachimijiogan containing benzoylmesaconine, benzoylhypaconine, and 14-anisoylaconine specified as marker compounds by the Japanese Pharmacopoeia for quantification for quality control, and evaluated these components as possible marker compounds for bioequivalence.Six healthy adult males were randomly divided into two groups, and an oral administration crossover study was performed. Changes in the plasma concentrations of 10 components (benzoylmesaconine, benzoylhypaconine, 14-anisoylaconine, alisol A, alisol A monoacetate, alisol B, alisol B monoacetate, loganin, morroniside, and paeoniflorin) were evaluated. As a result, the plasma concentration of each component in both the decoction and extract preparation varied among blood collection sites. A t-test revealed a significant difference (p<0.01) in the plasma concentration of benzoylhypaconine 4 h after administration, a significant difference (p<0.05) in the plasma concentration of alisol A monoacetate 1 h after administration, and a significant difference (p<0.05) in the plasma concentration of loganin 4 h after administration, for the decoction and the extract. However, significant differences in the plasma concentrations of other constituents were not noted for the decoction and extract.Alisol B and alisol B monoacetate could not be quantified due to an inadequate SN ratio (SN rate 10 or more). Analysis of variance for 8 components after excluding alisol B and alisol B monoacetate showed a significant difference (p<0.05) in the area under the blood concentration-time curve (AUC0-8) for benzoylmesaconine in the subjects’ neck. The preparation, time and subjects did not differ significantly as a factor, so the statistical power (1-β) was calculated (except for alisol B and alisol B). Both the peak plasma concentration (Cmax) and AUC0-8 values for all 8 components had inadequate (< 80%) statistical powers (1-β).Next, the number of subjects needed to achieve sufficient statistical power was estimated based on the obtained results. The statistical powers of both Cmax and AUC0-8 were adequate (≧ 80%) when the number of subjects (1 group) was ≧ 24 (1 group) for benzoylmesaconine, ≧ 25 for 14-anisoylaconine, and ≧ 24 for alisol A. On the other hand, the statistical power was inadequate even when the number of subjects was 61 (1 group) for benzoylhypaconine, alisol A monoacetate, loganin, paeoniflorin, or morroniside.The contents of alisols have been reported to vary in Alisma Tuber. Considering conversion due to metabolism, alisol A is also difficult to use as a marker compound. Therefore, in this prescription, benzoylmesaconine and 14-anisoylaconine may be appropriate marker compounds.