Absorption and metabolism of three monoester-diterpenoid alkaloids in Aconitum carmichaeli after oral administration to rats by HPLC–MS

Hai, Zhang; Wu, Qiong; Li, Wuhong; Sun, Shi; Zhang, Wen; Zhu, Zhenyu; Zhang, Guoqing; Chai, Yifeng

doi:10.1016/j.jep.2014.04.039

Cited by 23 publications

(12 citation statements)

References 15 publications

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“…Caco-2 cell line was obtained from the American Type Culture Collection (Manassas, VA, USA). Caco-2 cell transport experiment was performed according to the previously reported method [18,19]. In brief, Caco-2 cells were cultured in DMEM high glucose media containing 15% FBS, 1% NEAA and 100 U·mL −1 penicillin and streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Absorption and Metabolism Characteristics of Triptolide as Determined by a Sensitive and Reliable LC-MS/MS Method

Gong

Cao

2015

Molecules

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Abstract:In this research, a sensitive and reliable LC-MS/MS method was developed and applied to determine the concentration of triptolide in rat plasma, microsomes, and cell incubation media. The absolute oral bioavailability of triptolide is 63.9% at a dose of 1 mg·kg −1. In vitro, the bidirectional transport of triptolide across Caco-2 cells was studied. A markedly higher transport of triptolide across Caco-2 cells was observed in the basolateral-to-apical direction and was abrogated in the presence of the P-gp inhibitor, verapamil. The result indicated that P-gp might be involved in the absorption of triptolide in intestinal. The metabolic stability was also investigated using human liver microsome incubation systems in vitro. In HLMs, incubations with an initial triptolide concentration of 1 μM resulted in an 82.4% loss of substrate over 60 min, and the t1/2 was 38 min, which indicated that triptolide was easily metabolized in human liver microsomes. In conclusion, the absolute oral bioavailability of triptolide in plasma, transport across Caco-2 cell monolayers, and metabolic stability in human liver microsomes were systematically investigated by using a sensitive and reliable LC-MS/MS method. OPEN ACCESSMolecules, 2015, 20 8929

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Section: Methodsmentioning

confidence: 99%

Absorption and Metabolism Characteristics of Triptolide as Determined by a Sensitive and Reliable LC-MS/MS Method

Gong

Cao

2015

Molecules

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“…The rat liver microsome incubation experiment was performed according to the method previously reported. [25] In brief, except for NADPH-generating system (10 mM G-6-P, 1 mM NADP + , 4 mM magnesium chloride, 1 unit·ml -1 of G-6-PDH), 10 μL rat liver microsome (20 mg·mL -1 ), 4 μL drug solution (100 μM) and 366 μL PBS buffer (0.1 M, pH 7.4) were added to the centrifuge tubes on ice. The sample at t = 0 was achieved by removing the 95 μL incubation mixture, addition 5 μL PBS buffer and mixing with 300 μL acetonitrile.…”

Section: Excretion Study In Ratsmentioning

confidence: 99%

“…Some researchers have reported that Aconitum alkaloids were absorbed very quickly while the bioavailability was very low. [12,[18][19][20] Although many pharmacological studies on Aconitum alkaloids have been reported, [21][22][23][24][25] there are few systematic studies available on the pharmacokinetic characteristics and disposal process of the three forms of Aconitum alkaloids. The aim of this study was to determine the biological activities of three forms of Aconitum alkaloids in rat plasma, urine, faeces, and different tissues after oral administration by liquid chromatographytandem mass spectrometry (LC-MS/MS), investigate their disposal process in vivo, and clarify their pharmacokinetic parameters, absorption and metabolic stability by using a Caco-2 cell monolayer model and rat liver microsome incubation system in vitro, hoping that this study would provide references for rational clinical use of the Aconitum tuber, and for further research on the pharmacology or toxicology of this medicinal plant.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biological activities and pharmacokinetics of aconitine, benzoylaconine, and aconine after oral administration in rats

Hai

Sun

Zhang

et al. 2015

Drug Testing and Analysis

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Aconitine (AC), benzoylaconine (BAC), and aconine (ACN) are three representative alkaloids in Aconitum tubers. Knowing that the drug disposal process in vivo is closely related to the toxicity and efficacy of a drug, it is important to classify the disposal properties of these alkaloids. In this study, the pharmacokinetics of the three alkaloids was investigated. The results showed that the three alkaloids could be quickly absorbed, especially BAC, whose Tmax was 0.31 ± 0.17 h. Their Cmax was 10.99, 3.99, and 4.29 ng·mL(-1) respectively, indicating that AC had better absorption than BAC and ACN. Subsequently, we further investigated their absorption mechanism using the Caco-2 cell monolayer model in vitro. The results showed that they were poorly absorbed, and the absorption of AC and BAC was inhibited by P-gp, while the absorption of ACN was in a form of passive diffusion. The t1/2 of AC, BAC and ACN was 1.41, 9.49, and 3.32 h, respectively, indicating that the metabolic or excretion rate of AC was quicker than that of BAC and ACN. Therefore, their metabolic stability was further investigated by using rat liver microsomes in vitro, which showed that AC was easier to be metabolized than BAC and ACN. The excretion experiments showed that AC and ACN were primarily excreted in urine, while BAC was excreted in faeces. In addition, the results of tissue distribution experiments showed that the three alkaloids distributed throughout all the organs, although the distribution rate of AC was slower than that of BAC and ACN. Copyright © 2015 John Wiley & Sons, Ltd.

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“…The results provided a chemical material basis for further network pharmacological analysis in the present studies. Previous studies also revealed the role of absorption, distribution, metabolism and excretion of the three herbs, as well as their synergistic effects in SND 38 39 40 . In the present study, we constructed a cardiovascular-diseases (CVD) specific database, with an integrated chemogenomics knowledgebase consisting of chemicals, genes/protein targets, signaling pathways information and our established chemoinformatics tools 18 22 28 .…”

mentioning

confidence: 92%

Cardiovascular Disease Chemogenomics Knowledgebase-guided Target Identification and Drug Synergy Mechanism Study of an Herbal Formula

Zhang

Ma²,

Feng³

et al. 2016

Sci Rep

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Combination therapy is a popular treatment for various diseases in the clinic. Among the successful cases, Traditional Chinese Medicinal (TCM) formulae can achieve synergistic effects in therapeutics and antagonistic effects in toxicity. However, characterizing the underlying molecular synergisms for the combination of drugs remains a challenging task due to high experimental expenses and complication of multicomponent herbal medicines. To understand the rationale of combination therapy, we investigated Sini Decoction, a well-known TCM consisting of three herbs, as a model. We applied our established diseases-specific chemogenomics databases and our systems pharmacology approach TargetHunter to explore synergistic mechanisms of Sini Decoction in the treatment of cardiovascular diseases. (1) We constructed a cardiovascular diseases-specific chemogenomics database, including drugs, target proteins, chemicals, and associated pathways. (2) Using our implemented chemoinformatics tools, we mapped out the interaction networks between active ingredients of Sini Decoction and their targets. (3) We also in silico predicted and experimentally confirmed that the side effects can be alleviated by the combination of the components. Overall, our results demonstrated that our cardiovascular disease-specific database was successfully applied for systems pharmacology analysis of a complicated herbal formula in predicting molecular synergetic mechanisms, and led to better understanding of a combinational therapy.

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Absorption and metabolism of three monoester-diterpenoid alkaloids in Aconitum carmichaeli after oral administration to rats by HPLC–MS

Cited by 23 publications

References 15 publications

Absorption and Metabolism Characteristics of Triptolide as Determined by a Sensitive and Reliable LC-MS/MS Method

Absorption and Metabolism Characteristics of Triptolide as Determined by a Sensitive and Reliable LC-MS/MS Method

Biological activities and pharmacokinetics of aconitine, benzoylaconine, and aconine after oral administration in rats

Cardiovascular Disease Chemogenomics Knowledgebase-guided Target Identification and Drug Synergy Mechanism Study of an Herbal Formula

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