Profiling of the Compounds Absorbed in Human Plasma and Urine after Oral Administration of a Traditional Japanese (Kampo) Medicine, Daikenchuto

Iwabu, Jun; Watanabe, Junko; Hirakura, Kazuhiro; Ozaki, Yoshinori; Hanazaki, Kazuhiro

doi:10.1124/dmd.110.033589

Cited by 42 publications

(48 citation statements)

References 45 publications

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“…Details of preparation of standard solutions and quality control samples, instrumentation, analytical conditions, and validation of the analytical method for TU‐100 ingredients were described in a previous study (Iwabu et al. 2010). Diagrams of metabolic pathways of major ginseng ingredients are shown in Figures S1A and B.…”

Section: Methodsmentioning

confidence: 99%

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: Methodsmentioning

confidence: 99%

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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“…An Oasis HLB Elution Plate (Nihon Waters K.K, Tokyo, Japan) was used as the solid-phase extraction plate. The isolation, synthesis, and identification of the six authentic standards of the TJ-100 ingredients were described in a previous article (Iwabu et al, 2010). The structural formulas of the authentic standards are provided in Supplemental Fig.…”

Section: Methodsmentioning

confidence: 99%

“…The concentrations of six TJ-100 ingredients were determined according to the method reported by Iwabu et al (2010) with modification. In brief, 200 l of the plasma samples were mixed with 200 l of 0.1 M hydrochloric acid, 10 l of internal standard solution (schizandrin: 10 ng/ml for HAS and HBS; nonivamide: 10 ng/ml for 6S and 10S; and asiaticoside: 100 ng/ml for GRB1 and GRG1) and 10 l of water-acetonitrile [7:3 (v/v)].…”

Section: Methodsmentioning

confidence: 99%

“…To solve these problems, we have conducted preliminary clinical trials to obtain the profiles of compounds absorbed in the plasma and urine after a single oral administration of 15 g of TJ-100 in four healthy volunteers (Iwabu et al, 2010). In that study, we constructed a liquid chromatography-tandem mass spectrometry analysis to detect as many compounds as possible and successfully identified 44 ingredients of TJ-100.…”

Section: Introductionmentioning

confidence: 99%

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

Munekage¹,

Kitagawa²,

Ichikawa³

et al. 2011

Drug Metab Dispos

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ABSTRACT:The pharmacokinetics of daikenchuto (TJ-100), a pharmaceuticalgrade traditional Japanese medicine, were investigated in healthy Japanese volunteers after a single oral administration of 2.5-, 5-, and 10-g doses. Six ingredients [hydroxy-␣-sanshool (HAS), hydroxy-␤-sanshool (HBS), [6]-shogaol (6S), [10]-shogaol (10S), ginsenoside Rb 1 (GRB1), and ginsenoside Rg 1 (GRG1)] of TJ-100 were determined by using liquid chromatography-tandem mass spectrometry. The results indicated that HAS, an ingredient derived from Zanthoxylum piperitum fruit, exhibited the highest plasma concentration among the six ingredients investigated. The plasma concentrations of HAS, HBS, 6S, and 10S reached the maximum concentration (approximately 400, 80, 0.14, and 0.6 ng/ml, respectively, after a 5-g administration of TJ-100) within 30 min after administration, and the mean half-life was approximately 2 h. Thus, these compounds were rapidly absorbed and eliminated. The plasma concentration of GRB1 reached the maximum concentration (2 ng/ml after a 5-g administration of TJ-100) at approximately 4 h after administration and the half-life of GRB1 was approximately 40 h. The plasma concentration of GRG1 was extremely low (<0.023 ng/ml). The pharmacokinetics of HAS, HBS, 6S, and 10S, were linear within the range of 2.5 to 10 g/day of TJ-100. On the other hand, the kinetics of GRB1 and GRG1 were not proportional to dosage, and plateauing was observed.

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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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Profiling of the Compounds Absorbed in Human Plasma and Urine after Oral Administration of a Traditional Japanese (Kampo) Medicine, Daikenchuto

Cited by 42 publications

References 45 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

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

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

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