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

Mutoh, T.; Igarashi, Yasushi; Nishimura, Hiroaki; Watanabe, Junko; Maemura, Kazuya; Kase, Yoshio

doi:10.3390/molecules20022100

Cited by 12 publications

(13 citation statements)

References 14 publications

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“…In vitro studies using rat and human liver microsomes reported that GM was metabolized into at least 13 metabolites including hydroxylated, dehydrogenated, hydroxylated + dehydrogenated, demethylated, and hydration forms by several CYP isoforms, and CYP3A4 was found to mainly contribute to GM metabolism [ 58 , 59 ]. Parent/unchanged GM was detected in both plasma and brain of rats after orally administered YKS, and demonstrated that GM was able to cross the blood-brain barrier (BBB) in an in vitro BBB assay [ 13 , 14 ].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook

Ikarashi

Sekiguchi

Mizoguchi

2018

CMC

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Background: Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symp-toms of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM has been related to various serotonin (5-HT) receptor subtypes.Objective: The aim of this article is to review the binding characteristics of GM to the 5-HT receptor sub-types in the brains using our own data and previous findings.Methods: Competitive receptor-binding and agonist/antagonist activity assays for several 5-HT receptor subtypes were performed. Moreover, the articles describing pharmacokinetics and brain distribution of GM were searched in PubMed.Results: GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4, 5-HT5A, 5-HT6, and 5-HT7. Among these receptors, GM had partial agonistic activity for 5-HT1A receptors and antagonistic activity for 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors. Also, GM was me-tabolized by various CYP isoforms, mainly CYP3A4. Parent/unchanged GM was detected in both the blood and brain of rats after oral administration of YKS. In the brains, GM was presumed to bind to 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT7 receptors on neuron-like large cells mainly in the frontal cor-tex.Conclusion: These results suggest that GM is a pharmacologically important alkaloid that regulates vari-ous serotonergic activities or functions by binding to multiple 5-HT receptor subtypes. Thus, this review provides recent 5-HT receptor-related evidence that GM is partly responsible for pharmacological effects of YKS.

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Section: Pharmacokineticsmentioning

confidence: 99%

Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook

Ikarashi

Sekiguchi

Mizoguchi

2018

CMC

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“…Earlier publications have described methods, including high-performance liquid chromatography with ultra-violet detection [21], high-performance liquid chromatography with DAD detection [22], and high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry [23,24] that have been used in the qualitative or quantitative analysis of alkaloids from the genus Coptis, single herb or herbs used together in couples (Coptis-Evodia herb couple [25], scutellaria-coptis herb couple [26]), at most six or seven alkaloids simultaneously. However, to date, there are few publications concerning CCY , especially the pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous Determination of Eight Alkaloids in Rat Plasma by UHPLC-MS/MS after Oral Administration of Coptis deltoidea C. Y. Cheng et Hsiao and Coptis chinensis Franch

et al. 2016

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A ultra-high performance liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) method was successfully developed and validated for the identification and determination of eight alkaloids: tetrahydropalmatine (A); palmatine (B); magnoflorine (C); columbamine (D); berberine (E); worenine (F); berberrubine (G) and coptisine (H) in rat plasma, which are the active components in Coptis deltoidea C. Y. cheng et Hsiao (CCY) and Coptis chinensis Franch (CF). The chromatographic separation of analytes was successfully achieved on an Agilent SB-C 18 column (1.8 µm, 150 mmˆ2.1 mm) using a programme with a mobile phase consisting of acetonitrile and water containing 0.3% acetic acid at a flow rate of 0.25 mL/min. The analytes were detected with a triple quadrupole tandem MS in multiple reaction monitoring (MRM) mode and an electrospray ionization (ESI) source in positive mode. The validated method showed good linearity over a wide concentration range (r 2 > 0.991), and lower limits of quantification (LLOQ) less than 1.1 ng/mL for all analytes, and matrix effects ranged from 85.2% to 106.8%. The mean extraction recoveries were no less than 86.4%, and the precision and accuracy were within the acceptable limits. All analytes were proven to be stable during sample storage and analysis procedures. The method validation results demonstrated that the proposed method was sensitive, specific, and reliable, which could lay a foundation for the pharmacokinetic study of eight analytes after oral administration of CCY and CF in subsequent studies.

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“…Compared with the YKS-alone group, the peak concentrations of GM in the plasma (Figure 1B) and brain (Figure 1F) of the MEM + YKS-combined group tended to be increased (approximately 40% and 40% in the plasma and brain), although the time-dependent changes in GM concentrations between both groups were not statistically significant (two-way ANOVA, group factor: F 1, 25 = 2.98, p = 0.096 in the plasma; and F 1, 25 = 4.09, p = 0.054 in the brain). In addition to this result, GM has been reported to be metabolized into several metabolites in rats and humans [29,30], and its metabolism is performed mainly by CYP3A4 in humans [30]. On the other hand, an in vitro study has been showed that MEM does not induce or inhibit the activity of CYPs, epoxide hydrolase, flavin-containing monooxygenase, and UDP-glucuronosyltransferase [1].…”

Section: Resultsmentioning

confidence: 99%

“…MEM is almost entirely excreted in the urine via organic cation transporter 2 [28]. On the other hand, not all metabolites of ingredients in YKS are known, and in vitro studies using rat and human liver microsomes have reported that GM is metabolized into several metabolites in both species [29,30]. Furthermore, cytochrome P450 (CYP) 3A4 was shown mainly to contribute to GM metabolism in human liver microsomes [30].…”

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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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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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

Cited by 12 publications

References 14 publications

Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook

Serotonin Receptor Binding Characteristics of Geissoschizine Methyl Ether, an Indole Alkaloid in Uncaria Hook

Simultaneous Determination of Eight Alkaloids in Rat Plasma by UHPLC-MS/MS after Oral Administration of Coptis deltoidea C. Y. Cheng et Hsiao and Coptis chinensis Franch

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

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