Systematic Analysis of Post-Administrative Saiboku-To Urine by Liquid Chromatography to Determine Pharmacokinetics of Traditional Chinese Medicine

Homma, Masato; Oka, Kitaro; Taniguchi, Chizu; Niitsuma, Tomoyuki; Hayashi, Tohru

doi:10.1002/(sici)1099-0801(199705)11:3<125::aid-bmc631>3.0.co;2-l

Cited by 47 publications

(39 citation statements)

References 20 publications

(22 reference statements)

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“…Synthesis of Davidigenin. Davidigenin (DA) was synthesized by hydrogenation of ILG according to the literature (Homma et al, 1997). Fifty milligrams of ILG was dissolved in 10 ml of ethanol and hydrogenated over palladium-charcoal (0.1 g) under vigorous stirring at room temperature for 2 h. After filtration and evaporation of the solvent, the residue was purified on a silica gel column and eluted with petroleum ether-acetone to obtain DA (43 mg, 86% yield).…”

Section: Downloaded Fromsupporting

confidence: 91%

“…Most of these studies were focused on single licorice compounds such as glycyrrhizic acid (Makino et al, 2008), liquiritigenin (Shimamura et al, 1993), and isoliquiritigenin (Guo et al, 2008a,b;Cuendet et al, 2010). Some other studies attempted to detect the in vivo metabolites after licorice extracts were administered (Homma et al, 1997;Zuo et al, 2003;Hou et al, 2005). However, only a few compounds were detected in most reports.…”

Section: Introductionsupporting

confidence: 86%

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From Single Compounds to Herbal Extract: A Strategy to Systematically Characterize the Metabolites of Licorice in Rats

Cheng¹,

Qiao²,

Wang³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Because of the complicated chemical composition of traditional Chinese medicines (TCMs), their metabolic study has been a great challenge, especially when they are used in the traditional way, i.e., clinical oral dose of water decoction. Poor understanding of metabolic pathways and too low metabolite concentrations to be detected in biosamples are the major hurdles. In the present work, a three-step strategy was proposed to systematically characterize in vivo metabolites of TCMs at a normal clinical dosage. Licorice, one of the most popular TCMs, was studied as a model. First, 10 representative compounds of licorice were administered to rats separately. A total of 68 metabolites were characterized by highperformance liquid chromatography coupled with diode-array detection and electrospray ionization tandem mass spectrometry and liquid chromatography (LC)/quadrupole time-of-flight-mass spectrometry (MS) analyses, together with enzyme hydrolysis. Among these, 13 compounds were confirmed by comparison with reference standards, including the 10 administered licorice compounds. Second, a high dose (equivalent to 20-fold clinical dosage) of licorice water extract was administered, and 22 more metabolites were characterized. Finally, these metabolites (including constituents of licorice) were determined by a highly sensitive and selective LC/selected reaction monitoring-MS method when the licorice water decoction was orally administered to rats at a clinical dosage (0.9 g crude drug/kg). A total of 42 metabolites in plasma and 62 metabolites in urine were detected. This is the first attempt to fully profile the in vivo metabolites of licorice at a normal clinical dosage.

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confidence: 91%

Section: Introductionsupporting

confidence: 86%

From Single Compounds to Herbal Extract: A Strategy to Systematically Characterize the Metabolites of Licorice in Rats

Cheng¹,

Qiao²,

Wang³

et al. 2011

Drug Metab Dispos

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“…We report the development of an LC-MS/MS-based method that can simultaneously quantify six licorice flavonoids in rat plasma. An earlier liquid chromatography-ultraviolet (LC-UV)-based method for quantification of liquiritigenin in urine was reported [7], but it may not be suitable for plasma pharmacokinetic studies because of poor sensitivity.…”

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confidence: 99%

Simultaneous quantification of multiple licorice flavonoids in rat plasma

Liang

et al. 2007

J. Am. Soc. Mass Spectrom.

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Flavonoids are important naturally occurring polyphenols with antioxidant properties. In this study, we report the development of a liquid chromatography tandem mass spectrometry (LC-MS/MS)-based method capable of simultaneously quantifying multiple active licorice flavonoids (including liquiritin apioside, liquiritin, liquiritigenin, isoliquiritin apioside, isoliquiritin, and isoliquiritigenin) in plasma. Electrospray ionization was used to efficiently generate precursor deprotonated molecules of all the analytes and the [M-H] Ϫ ions were used to produce characteristic product ions for MS/MS analysis. We found that inclusion of a very low concentration of HCOONH 4 (0.01‰) in the LC mobile phase dramatically improved the detection limit for the tested flavonoids and decreased the interference by matrix effects, which have been referred to as "LC-electrolyte effects." Liquid-liquid extraction with ethyl acetate was effective for isolation of all the analytes and resulted in the lowest matrix effects of several tested sample cleanup methods. This bioanalytical method showed good linearity between 0.32 ng/mL and 1 g/mL analyte in 50-L plasma samples. The accuracy and precision at different analyte concentrations varied from 85 to 110% and from 0.8 to 8.8%, respectively. Finally, we demonstrated the applicability of this method in a pilot pharmacokinetic study of rats receiving an oral dose of Xiaochaihu-tang, an important Chinese herbal remedy for chronic hepatitis. The use of a low concentration of HCOONH 4 in the LC mobile phase could be used to improve LC-mass spectroscopy-or LC-MS/MS-based methods. (J Am Soc Mass Spectrom 2007, 18, 778 -782)

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“…7) Davidigenin was synthesized by hydrogenation of isoliquiritigenin. 8 Peripheral Blood Mononuclear Cell Culture PBMCs were separated from heparinized venous blood collected from healthy volunteers, as described previously. [9][10][11] The cells were suspended in RPMI-1640 medium containing 10% FBS, 100000 IU/l penicillin and 100 mg/l streptomycin at a density of 1ϫ10 6 cells/ml.…”

Section: Methodsmentioning

confidence: 99%

Induction of Apoptosis in Human Lung Fibroblasts and Peripheral Lymphocytes in Vitro by Shosaiko-to Derived Phenolic Metabolites.

Liu

Tanaka

Horigome

et al. 2002

Biological & Pharmaceutical Bulletin

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Shosaiko-to (TJ-9), a drug-extract preparation comprised of 7 kinds of herbal components, is one of the most commonly used Kampo medicines being mainly indicated for chronic liver injury in Japan. Recently, over 200 cases of interstitial pneumonia have been reported resulting from TJ-9 therapy.2,3) The cases of interstitial pneumonia have been noted to increase when treated with interferon (IFN)-a and TJ-9 at the same time.4) Accordingly, the combination has been contraindicated in Japan since 1994; however, the mechanisms of interstitial pneumonia induced by TJ-9 and IFN-a are not fully understood. It was observed that TJ-9 and IFN-a inhibited the proliferation of lung fibroblasts and increased the production of interleukin-6 (IL-6) by fibroblasts from healthy subjects and patients with idiopathic pulmonary fibrosis (IPF) in vitro.5) Although interstitial pneumonia induced by TJ-9 and/or IFN-a has been suggested to be caused by an allergic-immunological mechanism rather than toxicity, 4) other possible explanations remain to be investigated.Identification of the biologically active compounds might be a solution in clarifying the serious side effect of this crude drug. As possible candidates, 7 phenolic compounds have been found in human urine after administration of TJ-9 (Fig. 1). 6) They include medicarpin and liquiritigenin derived from Glycyrrhiza glabra; baicalin, baicalein, oroxylin A and wogonin from Scutellaria baicalensis; and davidigenin, a hydrogenated metabolite of liquiritigenin. Since these compounds are actually absorbed into the body and excreted in the urine as free and glucuronide conjugate forms, 7) we hypothesized that they would play an important role for the clinical effects of TJ-9. Therefore, in the current study, we investigated the effects of these 7 compounds and IFN-a on inducing apoptosis in human lung fibroblasts and peripheral Shosaiko-to is a Kampo medicine used for the treatment of chronic hepatitis in Japan. Lately, over 200 cases of interstitial pneumonia have been reported resulting from Shosaiko-to therapy, and the number of cases increased when patients were administrated interferon (IFN)-a a at the same time. However, the mechanisms of this Shosaiko-to implicated interstitial pneumonia are not fully understood. In this study, we examined by flow cytometry analysis the in vitro effects of 7 phenolic compounds (lignans and flavonoids), which were detected from human urine after administration of Shosaiko-to, and IFN-a a on inducing apoptosis in human lung fibroblasts and peripheral blood mononuclear cells (PBMCs). Among the 7 compounds, baicalein and medicarpin (10 m mg/ml) showed significant apoptosis-inducing effects on human PBMCs. In human lung fibroblasts, medicarpin exhibited a significantly higher activity to induce apoptosis compared to the control, and the percentage of cells undergoing apoptosis showed time-and dose-dependent increases. Baicalein (0.1 and 1 m mg/ml), liquiritigenin (10 m mg/ml) and davidigenin (10 m mg/ml) also showed significant effects after 96 h...

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Systematic Analysis of Post-Administrative Saiboku-To Urine by Liquid Chromatography to Determine Pharmacokinetics of Traditional Chinese Medicine

Cited by 47 publications

References 20 publications

From Single Compounds to Herbal Extract: A Strategy to Systematically Characterize the Metabolites of Licorice in Rats

From Single Compounds to Herbal Extract: A Strategy to Systematically Characterize the Metabolites of Licorice in Rats

Simultaneous quantification of multiple licorice flavonoids in rat plasma

Induction of Apoptosis in Human Lung Fibroblasts and Peripheral Lymphocytes in Vitro by Shosaiko-to Derived Phenolic Metabolites.

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