Simultaneous determination of gelsemine and koumine in rat plasma by UPLC‐MS/MS and application to pharmacokinetic study after oral administration of <i>Gelsemium elegans</i> Benth extract

Wang, Lin; Wen, Yanqing; Meng, Fan‐hao

doi:10.1002/bmc.4201

Cited by 13 publications

(17 citation statements)

References 13 publications

(15 reference statements)

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“…We optimized the UPLC-MS/MS method to quantify KM and the IS in rat plasma. We tuned the full-scan mass spectra and found that the signal intensity of the two analytes was more robust in the positive than in the negative ion mode, most likely because the nitrogen atoms in the alkaloid structure tend to be protonated (Chen et al, 2013;Wang et al, 2018b). Therefore, we adopted the positive ion mode throughout this study.…”

Section: Uplc-ms/ms Methods Development and Optimizationmentioning

confidence: 99%

“…Based on these data, three doses were selected for pharmacokinetic studies on aging-associated diseases during preclinical studies of KM. Since our preliminary experiments and published studies indicated that KM was rapidly absorbed, we added an early time-point (0.033 h) to the absorption phase (Wang et al, 2018b). Furthermore, we added two additional time-points near the C max in the equilibrium phase to more accurately assess plasma concentration and other parameters (Wang et al, 2018b).…”

Section: Dose Proportionality Pharmacokinetics Of Km In Adult Ratsmentioning

confidence: 99%

“…Pharmacokinetic profiling is vital for understanding the in vivo behavior and mechanism of action of a drug. On account of its diverse biological activities, many metabolic and excretion studies in rats (Chen et al, 2013;Wang et al, 2018a;Wang et al, 2018b), pigs (Yang et al, 2018;Liu et al, 2019), and goats (Cao et al, 2020;Zuo et al, 2020) have investigated the role of KM. However, the dose proportionality of KM following oral administration, particularly in aged individuals, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

Zhang

et al. 2020

Front. Pharmacol.

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Aging leads to changes in nearly all pharmacokinetic phases. Koumine (KM), an alkaloid derived from Gelsemium elegans Benth., is effective against age-associated chronic diseases, but its dose proportionality following oral administration in aged individuals remains unknown. Herein, we established and validated a simple method that requires low sample volumes to determine KM concentration in rats using ultra-performance liquid chromatography-tandem mass spectrometry. The maximum plasma concentration (C max) of 7 mg•kg −1 KM was~12-fold and~24-fold higher than that of 0.28 mg•kg −1 KM in adult and aged rats, respectively (P < 0.01). Time to reach C max (T max) for 7 mg•kg −1 KM was 4-fold longer in aged rats (P < 0.05). The area under the curve (AUC) of 7 mg•kg −1 KM was >17-fold and >43-fold higher than those of 0.28 mg•kg −1 KM in adult and aged rats, respectively (P < 0.01). The half-life (t 1/2) of 7 mg•kg −1 KM was over 4-fold longer than that of 0.28 mg•kg −1 KM in adult rats (P < 0.01). The t 1/2 of 1.4 and 7 mg•kg −1 KM were 1.5~2fold longer, than that of 0.28 mg•kg −1 KM in aged rats (P < 0.05). The clearance rate of 7 mg•kg −1 KM was significantly lower in aged than in adult rats (P < 0.05). For 7.0 mg•kg −1 KM, the C max in aged rats was higher than in adult rats during the T max period (P < 0.05). In aged rats, the AUC for KM was >2.5-fold higher (P < 0.05) and the t 1/2 was >60% longer than in adult rats (P < 0.05). These results help interpret the pharmacokinetics of KM in aging-associated diseases.

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Section: Uplc-ms/ms Methods Development and Optimizationmentioning

confidence: 99%

Section: Dose Proportionality Pharmacokinetics Of Km In Adult Ratsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

Zhang

et al. 2020

Front. Pharmacol.

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“…However, it also possesses inhibitory effects on splenocyte proliferation and the humoral immune response [ 9 ]. In the previous study, our group reported the pharmacokinetics study of gelsemine and koumine after oral administration of the extract of G. elegans [ 10 ], but the tissue distribution data in the literature is limited. Furthermore, there is no report about the influence of GU on the pharmacokinetics and tissue distribution of KM and we speculate that GU may have an impact on the pharmacokinetics of KM metabolized by inducing the CYP450 system.…”

Section: Introductionmentioning

confidence: 99%

Ultra-Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS)-Based Pharmacokinetics and Tissue Distribution Study of Koumine and the Detoxification Mechanism of Glycyrrhiza uralensis Fisch on Gelsemium elegans Benth.

et al. 2018

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Gelsemium elegans Benth. (G. elegans), which is a famous Chinese folk medicine, has been commonly used to treat certain types of skin ulcers and alleviate inflammation, headaches, and cancer pain. However, the extensive clinical use of G. elegans has been greatly hampered by its toxicity. As one of the most widely used herbal medicines, Glycyrrhiza uralensis Fisch, has a unique effect on detoxification of G. elegans. In the present study, a rapid and sensitive method using ultra-liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was established and validated for determination of koumine, the most abundant molecule among the alkaloids of G. elegans, in rat plasma, tissue, and liver microsome. The developed method was successfully applied to the pharmacokinetics, tissue distribution, and in vitro metabolism study in rat with or without pre-treated Glycyrrhiza uralensis Fisch extract. Meanwhile, the expression level of CYP3A1 mRNA was analyzed to explain the detoxification mechanism of Glycyrrhiza uralensis Fisch on G. elegans. As a result, our work demonstrated that Glycyrrhiza uralensis Fisch could significantly affect the pharmacokinetics and tissue distribution of koumine in rats. The detoxification mechanism of Glycyrrhiza uralensis Fisch on G. elegans may be its cytochrome enzyme up-regulation effect.

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“…There have been methods reported for the determination of Gelsemium alkaloids, including high performance liquid chromatography-tandem (HPLC) [15,16], ultraperformance liquid chromatography-quadrupole-time of flight mass spectrometry (UPLC-Q-TOF/MS) [17,18], liquid chromatography/tandem mass spectrometry (LC/MS/MS) [19][20][21][22][23], and ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) [24][25][26][27][28] in vivo. However, a method has not been found for the simultaneous determination of 11 Gelsemium alkaloids in rat plasma, and the toxicokinetics of 11 Gelsemium alkaloids (humantenirine, humantenine, akuammidine, gelsevirine, rankinidine, n-methoxyanhydrovobasinediol, gelsenicine, gelsemine, koumine, koumidine, and sempervirine) after intravenous administration has not been reported.…”

Section: Introductionmentioning

confidence: 99%

Toxicokinetics of 11 Gelsemium Alkaloids in Rats by UPLC-MS/MS

Shen

Wang

et al. 2020

BioMed Research International

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Gelsemium elegans (Gardn. & Champ.) Benth. is a plant belonging to the genus Gelsemium (family Gelsemiaceae), and its main components are alkaloids. It is a Chinese traditional medicinal plant and notoriously known as a highly toxic medicine. However, a method has not yet been found for the simultaneous detection of 11 Gelsemium alkaloids in rat plasma, and the toxicokinetics of 11 Gelsemium alkaloids after intravenous administration has not been reported. In this work, we have developed a sensitive and rapid method of ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) for the detection of 11 Gelsemium alkaloids in rat plasma. The toxicokinetic behavior was also investigated, so as to provide a reference of the scientific properties of Gelsemium elegans and improve the efficacy and safety of drugs. Sixty-six Sprague-Dawley rats were randomly divided into 11 groups, six rats in each group. Each group was intravenously given one alkaloid (0.1 mg/kg), respectively. A Waters UPLC BEH C18 column (50 mm×2.1 mm, 1.7 μm) was used for chromatographic separation. Methanol and water (containing 0.1% formic acid) were used for the mobile phase with gradient elution. Multiple reactions were monitored, and positive electrospray ionization was used for quantitative analysis. The precision was less than 16%, and the accuracy was between 86.9% and 113.2%. The extraction efficiency was better than 75.8%, and the matrix effects ranged from 88.5% to 107.8%. The calibration curves were in the range of 0.1–200 ng/mL, with a correlation coefficient (R2) greater than 0.995. The UPLC-MS/MS method was successfully applied to the toxicokinetics of 11 Gelsemium alkaloids in rats after intravenous administration (0.1 mg/kg for each alkaloid). The results of the toxicokinetics provide a basis for the pharmacology and toxicology of Gelsemium alkaloids and scientific evidence for the clinical use of Gelsemium alkaloids.

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Simultaneous determination of gelsemine and koumine in rat plasma by UPLC‐MS/MS and application to pharmacokinetic study after oral administration of Gelsemium elegans Benth extract

Cited by 13 publications

References 13 publications

Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

Ultra-Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS)-Based Pharmacokinetics and Tissue Distribution Study of Koumine and the Detoxification Mechanism of Glycyrrhiza uralensis Fisch on Gelsemium elegans Benth.

Toxicokinetics of 11 Gelsemium Alkaloids in Rats by UPLC-MS/MS

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