Pharmacokinetics of Daikenchuto, a Traditional Japanese Medicine (Kampo) after Single Oral Administration to Healthy Japanese Volunteers

Munekage, Masaya; Kitagawa, Hiroyuki; Ichikawa, Kengo; Watanabe, Junko; Aoki, Katsuyuki; Kono, Toru; Hanazaki, Kazuhiro

doi:10.1124/dmd.111.040097

Cited by 46 publications

(49 citation statements)

References 17 publications

(15 reference statements)

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“…Similar to previous studies in humans (Munekage et al. 2011), in SPF mice Rb1 was slowly absorbed, peaked at 2 h, and decreased slowly. After 24 h, over 80% of the peak Rb1 amount was still present in the blood.…”

Section: Resultsmentioning

confidence: 93%

Daikenchuto (TU‐100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K

Hasebe

Ueno

Musch

et al. 2016

Pharmacology Res & Perspec

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Many pharmaceutical agents not only require microbial metabolism for increased bioavailability and bioactivity, but also have direct effects on gut microbial assemblage and function. We examined the possibility that these actions are not mutually exclusive and may be mutually reinforcing in ways that enhance long‐term of these agents. Daikenchuto, TU‐100, is a traditional Japanese medicine containing ginseng. Conversion of the ginsenoside Rb1 (Rb1) to bioactive compound K (CK) requires bacterial metabolism. Diet‐incorporated TU‐100 was administered to mice over a period of several weeks. T‐RFLP and 454 pyrosequencing were performed to analyze the time‐dependent effects on fecal microbial membership. Fecal microbial capacity to metabolize Rb1 to CK was measured by adding TU‐100 or ginseng to stool samples to assess the generation of bioactive metabolites. Levels of metabolized TU‐100 components in plasma and in stool samples were measured by LC‐MS/MS. Cecal and stool short‐chain fatty acids were measured by GC‐MS. Dietary administration of TU‐100 for 28 days altered the gut microbiota, increasing several bacteria genera including members of Clostridia and Lactococcus lactis. Progressive capacity of microbiota to convert Rb1 to CK was observed over the 28 days administration of dietary TU‐100. Concomitantly with these changes, increases in all SCFA were observed in cecal contents and in acetate and butyrate content of the stool. Chronic consumption of dietary TU‐100 promotes changes in gut microbiota enhancing metabolic capacity of TU‐100 and increased bioavailability. We believe these findings have broad implications in optimizing the efficacy of natural compounds that depend on microbial bioconversion in general.

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Section: Resultsmentioning

confidence: 93%

Daikenchuto (TU‐100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K

Hasebe

Ueno

Musch

et al. 2016

Pharmacology Res & Perspec

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“…As reported previously in Japanese PK study (Munekage et al, 2011), nonlinearity was observed in AUC of GRB1, but dose-dependence in half-life was not; therefore, a nonlinear absorption model was assumed for the GRB1 analysis. As a result, nonlinear parameter (b) showed a significant value, and the AIC value indicated a better fit compared with the model not assuming the nonlinear parameter.…”

Section: Discussionmentioning

confidence: 91%

“…The concentrations of five DKT constituents-HAS, HBS, 6S, 10S, and GRB1-were determined by a validated liquid chromatography-tandem mass spectrometry method as reported by Munekage et al (2011). The limits of the quantification were 0.01 ng/ml for HAS, HBS, and GRB1 and 0.02 ng/ml for 6S and 10S.…”

Section: Methodsmentioning

confidence: 99%

“…Iwabu et al (2010) reported that 44 compounds derived from DKT were detected in the plasma and urine after oral administration of DKT by using the liquid chromatographytandem mass spectrometry. Moreover, Munekage et al (2011) reported the plasma concentration profiles of six pharmacologically active constituents of DKT-hydroxy-a-sanshool (HAS), hydroxyl-b-sanshool (HBS), 6-shogaol (6S), 10-shogaol (10S), ginsenoside Rb 1 (GRB1), and ginsenoside Rg 1 -in Japanese healthy volunteers.…”

Section: Introductionmentioning

confidence: 99%

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Population Pharmacokinetic Analysis of Daikenchuto, a Traditional Japanese Medicine (Kampo) in Japanese and US Health Volunteers

et al. 2013

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“…Moreover, hydroxyl-α-and hydroxyl-β-sanshool were detected in human plasma and urine after oral administration of Daikenchuto. 5,6) Consequently, in terms of delineating the mechanism of action of Daikenchuto, hydroxyl-α-and hydroxyl-β-sanshool are considered key compounds. Total synthesis of hydroxyl-α-and hydroxyl-β-sanshool has not been reported.…”

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confidence: 99%

Total Synthesis of Hydroxy-α- and Hydroxy-β-sanshool Using Suzuki–Miyaura Coupling

et al. 2012

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Here, we describe the first total synthesis of hydroxyl-α-and hydroxyl-β-sanshool, which involves Suzuki-Miyaura coupling (SMC). Hydroxy-α-sanshool (1) was synthesized by SMC of bromoalkyne 4 with boronate 3 followed by (Z)-selective reduction of the triple bond in the coupling product. Hydroxy-β-sanshool (2) was synthesized by regio-and (E)-selective conversion of 4 to iodoalkene 11 followed by SMC with 3.Key words hydroxy-α-sanshool; hydroxyl-β-sanshool; Suzuki-Miyaura coupling; Zanthoxylum Fruit; Daikenchuto Hydroxy-α-sanshool (1) was originally isolated as an unstable unsaturated aliphatic amide from the dried fruit of the Japanese pepper (Zanthoxylum piperitum).1) This compound elicits several biological effects such as activation of transient receptor potential channels 2) and inhibition of potassium channels.3) Hydroxy-β-sanshool (2), which is a geometric isomer of hydroxyl-α-sanshool (1), can also be isolated from the same dried fruit.4) Zanthoxylum Fruit is one of the crude drugs in Kampo formulae 'Daikenchuto.' Moreover, hydroxyl-α-and hydroxyl-β-sanshool were detected in human plasma and urine after oral administration of Daikenchuto.5,6) Consequently, in terms of delineating the mechanism of action of Daikenchuto, hydroxyl-α-and hydroxyl-β-sanshool are considered key compounds. Total synthesis of hydroxyl-α-and hydroxyl-β-sanshool has not been reported. However, a non-selective Wittig reaction has been used for the synthesis of α-and β-sanshool, which both lack a hydroxyl group. 7) In this paper, we describe the E/Z-selective total synthesis of hydroxyl-α-and hydroxyl-β-sanshool using Suzuki-Miyaura coupling (SMC).Our synthetic strategy is depicted in Chart 1. Both hydroxyl-α-sanshool (1) and hydroxyl-β-sanshool (2) could be synthesized from two common component parts: N-methyliminodiacetic acid (MIDA) boronate 3 and amide 4. After SMC between 4 and 3, (Z)-selective reduction of triple-bond in the resulting coupling product would lead to hydroxyl-α-sanshool (1). However, conversion of 4 to (E)-iodoalkene followed by SMC with 3 would afford hydroxyl-β-sanshool (2). Results and DiscussionHydroxy-α-sanshool (1) was convergently synthesized from three commercially available reagents; 1,2-epoxy-2-methylpropane (5), trans-2-bromovinylboronic acid MIDA ester (7) and 4-pentyn-1-ol (8). The amine fragment 6 8) was prepared by addition of dibenzylamine to 5 followed by deprotection of the benzyl group in 100% and 99% yield, respectively (Chart 2). The diene fragment 3 (MIDA boronate) was prepared from 7 and trans-1-propen-1-ylboronic acid by SMC in 77% yield (Chart 3). 9) Swern oxidation of 8 followed by Wittig reaction with methyl (triphenylphosphoranylidene) acetate was performed in a one-pot reaction in 88% yield. [10][11][12] This was followed by hydrolysis of the resulting ester to afford carboxylic acid 9 in 93% yield. Condensation 13) of the carboxylic acid 9 with the amine 6 followed by bromination 14) of the alkyne moiety in the amide gave bromoalkyne 4 in 73% and 97% yield, respectively. SMC of bromo...

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Pharmacokinetics of Daikenchuto, a Traditional Japanese Medicine (Kampo) after Single Oral Administration to Healthy Japanese Volunteers

Cited by 46 publications

References 17 publications

Daikenchuto (TU‐100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K

Daikenchuto (TU‐100) shapes gut microbiota architecture and increases the production of ginsenoside metabolite compound K

Population Pharmacokinetic Analysis of Daikenchuto, a Traditional Japanese Medicine (Kampo) in Japanese and US Health Volunteers

Total Synthesis of Hydroxy-α- and Hydroxy-β-sanshool Using Suzuki–Miyaura Coupling

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