Human intestinal bacteria responsible for the metabolism of saikosaponins

Metabolism of saikosaponins by human intestinal bacteria is discussed in view of the results obtained during the last years. Saikosaponins (SAPs) were converted to prosaikogenins and saikogenins in order by a human fecal suspension and by the bacterial strains, Eubacterium sp. A-44, Bifidobacterium sp. Saiko-1 and Saiko-2, isolated from human feces. From E. sp. A-44, two glycosidases responsible for the stepwise hydrolysis of SAPs were isolated and characterized as saikosaponin-hydrolyzing β-D-glucosidase and prosaikogenin-hydrolyzing β-D-fucosidase. After the oral administration of saikosaponin b_1 (Sb_1) to germ-free rats, no metabolites were detected in their plasma, cecal contents and cumulative feces. However, considerable amounts of prosaikogenin A and saikogenin A were detected when Sb_1 was orally given to conventional or the E. sp. A-44-infected gnotobiote rats. Fecal and cecal activities of hydrolyzing saikosaponins were found in the gnotobiote and conventional rats. These findings provided direct evidence that saikosaponins-hydrolyzing bacteria are necessary for the appearance of their biologically active metabolites in the systemic circulation

Transformation of shikonin by a cell-free extract of Eubacterium sp. A-44, a human intestinal bacterium

For the purpose of investigating the metabolic processes of shikonin (1) by human intestinal bacteria, we prepared a sonicated bacterial cell suspension and a crude enzyme preparation from Eubacterium sp. A-44, one of the intestinal bacteria capable of transforming 1 to various metabolites. After anaerobic incubation with the suspension for 1 hr, most of 1 was transformed to prometaboshi-konin (2), and metaboshikonins I (3) and II (4). However, under aerobic conditions, the dimers, shikometabolins A (5) and B (6), were predominantly formed. In the presence of the crude enzyme preparation, formation of 2-4 was inhibited by oxygen, but markedly enhanced by the addition of NADH. On the other hand, formation of 5 and 6 was appreciably accelerated by the addition of NAD^+. In the absence of the crude enzyme preparation, NADH and/or NAD^+ showed no ability to transform 1 to the any metabolites, as in the case of a thermally inactivated preparation. Accordingly, the two different metabolic processes leading to compounds 2-4 and com-pounds 5 and 6 by Eubacterium sp. A-44 are concluded to be enzyme-dependent in the presence of NADH and NAD^+. ヒト腸内細菌による紫根成分shikoninの代謝過程を研究する目的でshikonin(1)を種々の代謝物に変換する腸内細菌Eubacterium sp.A-44の細胞破砕懸濁液及び粗酵素標品を調製した。この粗酵素標品とshikonin(1)を嫌気条件下で1時間インキュベーションすると,shikonin(1)のほとんどはprometaboshikonin(2)およびmetaboshikonin I(3),II(4)に変換された。しかしながら,好気条件下ではshikometabolin A(5),B(6)などの二量体が生成した。化合物2-4の生成は,酸素によって阻害され,NADHの添加により増強した。一方,化合物5,6の生成はNAD^+の添加により増加した。加熱処理した場合と同様,粗酵素標品を除去した場合は,NADH,NAD^+を添加してもshikoninの変換は起こらなかった。したがって,NADHやNAD^+の存在下での化合物2-4や化合物5,6への変換過程は酵素反応によって触媒されることを示している

Pharmacokinetic study of Paeoniflorin Paeonimetabolin-I and Glycyrrhetic acid in humans after oral administration of Paeony Root, Glycyrrhiza and Shakuyaku-kanzo-to (Shao-Yao-Gan-Cao-Tang)

The pharmacokinetics of Paeoniflorin (PF) , Paeonimetabolin-I (PM-I) and Glycyrrhetic acid (GA) after oral administration of the decoction of Paeony Root (PR) and Glycyrrhiza (GR) and Shakuyaku-kanzo-to (Shao-Yao-Gan-Cao-Tang ; SK) were studied using human subjects. Concerning the intra- and inter-individual variability of PF and PM-I after oral administration of SK, each inter-individual coefficient of variation (CV) of the pharmacokinetic parameters was larger than its intra-individual CV. There was no significant correlation between each pharmacokinetic parameter and each subject\u27s physiques. These results suggested that a large inter-individual variability were not caused by differences in the subjects\u27 physiques. Regarding a comparison of the pharmacokinetic parameters, AUC and Cmax of PF of PR were significantly higher than those of SK, and MRT and Tmax of PM-I of SK were significantly longer than those of PR. AUC of GA of SK was significantly higher than those of GR. There is the possibility that PR would be better than SK when a stronger efficacy of PR is expected in a short time, and SK would be beter than PR when a longer efficacy of PR or a stronger efficacy of GR is expected. ヒト健常人において芍薬・甘草・芍薬甘草湯経口投与時のペオニフロリン(PF),ペオニメタボリン-I(PM-I),グリチルレチン酸(GA)の葉物動態の研究を施行した。芍薬甘草湯投与後のPF,PMIの個体内・個体間変動については,各々の個体問変動係数が個体内変動係数よりも大きく,また,全ての薬物動態の各パラメータと被験者の体格との間には相関はみられなかった。芍薬・甘草と芍薬甘草湯との比較では,芍薬のPFのAUC,Cmaxが芍薬甘草湯のものに比較して有意に高値を示し,芍薬甘草湯のPM-IのMRT,Tmaxが芍薬に比較して有意に長かった。また,芍薬甘草湯のGAのAUCは甘革単独投与のものに比較して有意に高値を示した。このことから,短時間に芍薬のより強い効果を期待する際には芍薬単独で用い,芍薬成分のより長い効果や甘草成分のより強い効果を期待する際には芍薬甘草湯として投与する方がよい可能性がある