The metabolism of YiGan San and subsequent pharmacokinetic evaluation of four metabolites in rat based on liquid chromatography with tandem mass spectrometry

Gai, Yanan; Chen, Han; Liu, Wenyuan; Feng, Feng; Xie, Ning

doi:10.1016/j.jchromb.2014.09.033

Cited by 10 publications

(16 citation statements)

References 19 publications

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“…Most MEM absorbed into the blood was demonstrated to be excreted from the kidney into urine as an unchanged form, without being metabolized by CYPs [24]. On the other hand, the metabolism and excretion of GM and ILQG have not been completely elucidated, but our results demonstrating the excretion of both ingredients into urine are similar to those reported previously [32,44]. To excrete orally administered ingredients into the urine, the ingredients must first be absorbed into the blood.…”

Section: Resultssupporting

confidence: 88%

“…In a clinical study, seven-day continuous administration of YKS did not affect the activity of CYP1A2, CYP2D6, CYP3A, xanthine oxidase, or N -acetyltransferase 2 [31]. GM was also reported to be excreted in the urine [32]; however, it is not known whether the ingredients of YKS, including GM, are substrates of their transporters, and whether they induce or inhibit the transporters.…”

Section: Introductionmentioning

confidence: 99%

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Basic Study of Drug-Drug Interaction between Memantine and the Traditional Japanese Kampo Medicine Yokukansan

et al. 2018

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Several basic pharmacokinetic and pharmacological studies were conducted as part of a group of studies to clarify the drug-drug interaction (DDI) between memantine (MEM), a drug used to treat Alzheimer’s disease, and yokukansan (YKS), a traditional Japanese Kampo medicine used to treat behavioral and psychological symptoms of dementia. The pharmacokinetic studies showed that there were no statistically significant differences in MEM concentrations in the plasma, brain, and urine between mice treated with MEM alone and with MEM plus YKS. Regarding candidate active ingredients of YKS, there were also no statistically significant differences in concentrations of geissoschizine methyl ether in the plasma and brain, urine, glycyrrhetinic acid in the plasma, and isoliquiritigenin in the urine, in mice treated with YKS alone or with MEM plus YKS. The pharmacological studies showed that isoliquiritigenin, which has an N-methyl-d-aspartic acid (NMDA) receptor antagonistic effect, did not affect the inhibitory effect of MEM on NMDA-induced intracellular Ca2+ influx in primary cultured rat cortical neurons. Moreover, YKS did not affect either the ameliorative effects of MEM on NMDA-induced learning and memory impairment, or the MEM-induced decrease in locomotor activities in mice. These results suggest that there is probably no pharmacokinetic or pharmacological interaction between MEM and YKS in mice, but more detailed studies are needed in the future. Our findings provide important information for future studies, to clarify the DDI more regarding the efficacy and safety of combined use of these drugs in a clinical situation.

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Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Basic Study of Drug-Drug Interaction between Memantine and the Traditional Japanese Kampo Medicine Yokukansan

et al. 2018

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“…M4-1 and M4-2 might also have 10- and 11-mono-hydroxy forms. More recently, 18-hydroxy GM was identified as the metabolite of GM in rat urine administrated with yokukansan [ 11 ]. M4-3 is predicted to be an oxidation metabolite at the side chain moiety containing C-18.…”

Section: Resultsmentioning

confidence: 99%

“…The compound 11-hydroxyyohimbine possesses the same α-2-adrenoceptor blocking activity as yohimbine [ 10 ]. More recently, the metabolism of yokukansan in rat urine was investigated, and 18-hydroxy GM was identified as the metabolite of GM [ 11 ]. However, the other metabolites of GM except for 18-hydroxy GM were not detected in rat urine.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Profiling of the Uncaria Hook Alkaloid Geissoschizine Methyl Ether in Rat and Human Liver Microsomes Using High-Performance Liquid Chromatography with Tandem Mass Spectrometry

et al. 2015

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Geissoschizine methyl ether (GM) is an indole alkaloid found in Uncaria hook, which is a galenical constituent of yokukansan, a traditional Japanese medicine. GM has been identified as the active component responsible for anti-aggressive effects. In this study, the metabolic profiling of GM in rat and human liver microsomes was investigated. Thirteen metabolites of GM were elucidated and identified using a high-performance liquid chromatography with tandem mass spectrometry method, and their molecular structures were proposed on the basis of the characteristics of their precursor ions, product ions, and chromatographic retention times. There were no differences in the metabolites between the rat and human liver microsomes. Among the 13 identified metabolites, there were two demethylation metabolites, one dehydrogenation metabolite, three methylation metabolites, three oxidation metabolites, two water-adduct metabolites, one di-demethylation metabolite, and one water-adduct metabolite followed by oxidation. The metabolic pathways of GM were proposed on the basis of this study. This study will be helpful in understanding the metabolic routes of GM and related Uncaria hook alkaloids, and provide useful information on the pharmacokinetics and pharmacodynamics. This is the first report that describes the separation and identification of GM metabolites in rat and human liver microsomes.

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“…So far, several studies reported the pharmacokinetics of rhynchophylline, isorhynchophylline, corynoxeine, and isocorynoxeine [12][13][14][15][16][17][18][19][20][21]. However, few studies reported the pharmacokinetics of hirsutine and hirsuteine.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic study on hirsutine and hirsuteine in rats using UPLC–MS/MS

Han

Lin

Cai

et al. 2019

Acta Chromatographica

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An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was established to determine hirsutine and hirsuteine in rat plasma. Pharmacokinetics of hirsutine and hirsuteine in rats after intravenous or oral administration has been investigated using this developed UPLC-MS/MS method, and bioavailability of the two drugs was calculated. Diazepam was used as internal standard, and UPLC BEH column (2.1 mm × 50 mm, 1.7 μm) was used at temperature of 40°C. The mobile phase was composed of acetonitrile and water (containing 0.1% formic acid) at a gradient elution flow rate of 0.4 mL/min. Nitrogen was used as desolvation gas (800 L/h) and conical gas (50 L/h). The multiple reaction monitoring (MRM) model was applied to quantitatively analyze hirsutine m/z 369 → 226, hirsuteine m/z 367 → 169.9, and diazepam (internal standard) m/z 285.1 → 193.3. Rat plasma samples were deproteinized using acetonitrile prior to UPLC-MS/MS analysis. Within the concentration range of 1-200 ng/mL, the linearity of hirsutine and hirsuteine in plasma was good (r > 0.995), and the lower limit of quantitation was 1 ng/mL. Relative standard deviations of intra-day precision for hirsutine and hirsuteine were ≤6.1% and ≤5.9%, respectively, and those of inter-day precision were ≤6% and ≤7.7%. Accuracy for hirsutine and hirsuteine ranged between 92.3% and 104.8%. Bioavailability of hirsutine and hirsuteine was 4.4% and 8.2%, respectively. The method is sensitive and fast with good selectivity and was successfully applied in the pharmacokinetic studies after intravenous and oral administration of hirsutine and hirsuteine.

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The metabolism of YiGan San and subsequent pharmacokinetic evaluation of four metabolites in rat based on liquid chromatography with tandem mass spectrometry

Cited by 10 publications

References 19 publications

Basic Study of Drug-Drug Interaction between Memantine and the Traditional Japanese Kampo Medicine Yokukansan

Basic Study of Drug-Drug Interaction between Memantine and the Traditional Japanese Kampo Medicine Yokukansan

Metabolic Profiling of the Uncaria Hook Alkaloid Geissoschizine Methyl Ether in Rat and Human Liver Microsomes Using High-Performance Liquid Chromatography with Tandem Mass Spectrometry

Pharmacokinetic study on hirsutine and hirsuteine in rats using UPLC–MS/MS

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