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1.
J Vet Pharmacol Ther ; 43(2): 208-214, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31943246

RESUMO

Sanguinarine (SA) is a benzo[c] phenanthridine alkaloid which has a variety of pharmacological properties. However, very little was known about the pharmacokinetics of SA and its metabolite dihydrosanguinarine (DHSA) in pigs. The purpose of this work was to study the intestinal metabolism of SA in vitro and in vivo. Reductive metabolite DHSA was detected during incubation of SA with intestinal mucosa microsomes, cytosol, and gut flora. After oral (p.o.) administration of SA, the result showed SA might be reduced to DHSA in pig intestine. After i.m. administration, SA and DHSA rapidly increased to reach their peak concentrations (Cmax , 30.16 ± 5.85, 5.61 ± 0.73 ng/ml, respectively) at 0.25 hr. Both compounds were completely eliminated from the plasma after 24 hr. After single oral administration, SA and DHSA rapidly increased to reach their Cmax (3.41 ± 0.36, 2.41 ± 0.24 ng/ml, respectively) at 2.75 ± 0.27 hr. The half-life (T1/2 ) values were 2.33 ± 0.11 hr and 2.20 ± 0.12 hr for SA and DHSA, respectively. After multiple oral administration, the average steady-state concentrations (Css ) of SA and DHSA were 3.03 ± 0.39 and 1.42 ± 0.20 ng/ml. The accumulation indexes for SA and DHSA were 1.21 and 1.11. The work reported here provides important information on the metabolism sites and pharmacokinetic character of SA. It explains the reasons for low toxicity of SA, which is useful for the evaluation of its performance.

2.
J Ethnopharmacol ; 252: 112617, 2020 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31988014

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal medicine contains hundreds of natural products, and studying their absorption, metabolism, distribution, and elimination presents great challenges. Gelsemium elegans (G. elegans) is a flowering plants in the Loganiaceae family. The plant is known to be toxic and has been used for many years as a traditional Chinese herbal medicine for the treatment of rheumatoid arthritis, neuropathic pain, spasticity, skin ulcers and cancer. It was also used as veterinary drugs for deworming, promoting animal growth, and pesticides. At present, studies on the metabolism of G. elegans have primarily focused on only a few single available reference ingredients, such as koumine, gelsemine and gelsedine. MATERIAL AND METHODS: The goal of this work is to elucidate the overall metabolism of whole G. elegans powder in goats using high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS). RESULTS: Analyses of plasma, urine and fecal samples identified or tentatively characterized a total of 44 absorbed natural products and 27 related produced metabolites. Gelsedine-type, sarpagine-type and gelsemine-type alkaloids were the compounds with the highest metabolite formation. In the present study, most natural products identified in G. elegans were metabolized through glucuronidation and oxidation. Hydrogenation, dehydrogenation and demethylation also occurred. CONCLUSION: To our knowledge, this is the first report of the metabolite profiling of the G. elegans crude extract in goats, which is of great significance for a safer and more rational application of this herbal medicine.

3.
J Anal Toxicol ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31993639

RESUMO

Gelsemium elegans (G. elegans) has been used in traditional Chinese medicine. This plant is highly toxic to humans, but can promote the growth of pigs and goats in the veterinary clinic. It is a very complex mixture containing tens or hundreds of different components. Therefore, multiple-component pharmacokinetic studies of G. elegans are a major challenge due to the lack of authentic standards of the components. The purpose of this study was to investigate the plasma pharmacokinetics of multiple components after a single oral dose of G. elegans in goat using a sensitive ultra-performance liquid chromatography coupled to tandem mass spectrometry method for the simultaneous semiquantification of multiple alkaloids without standards. The method was validated in terms of the specificity, LOD, LOQ, linearity, accuracy, precision and matrix effects. To validate the global pharmacokinetic characteristics, the results obtained from the semiquantitative analysis of three authentic compounds (gelsemine, koumine and humantenmine) were compared with the absolute quantification from our recently published method. The results showed that the two methods had similar analytical results, and the obtained values of Tmax, T1/2 and MRT0-t of the three alkaloids were similar between the two methods. In addition, the values of Cmax and AUC0-t of the three alkaloids after normalization were close to the real values, which indicated that this semiquantitative method could be used in the pharmacokinetic study of multiplecomponents. Then the pharmacokinetic parameters of 23 other G. elegans alkaloids in goats were obtained. The results suggested that the gelsedine-type alkaloids were the major active ingredients that predict and explain the efficacy and toxicity of G. elegans.

4.
Am J Chin Med ; 48(1): 127-142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31931594

RESUMO

Gelsemium elegans Benth. (G. elegans), a traditional Chinese medicine, has great potential as an effective growth promoter in animals, however, the mechanism of its actin remains unclear. Here, we evaluated the protective effects of koumine extract from G. elegans against lipopolysaccharide (LPS)-induced intestinal barrier dysfunction in IPEC-J2 cells through alleviation of inflammation and oxidative stress. MTT and LDH assays revealed that koumine significantly reduced LPS cytotoxicity. Transepithelial electrical resistance (TEER) and cell monolayer permeability assays showed that koumine treatment attenuated the LPS-induced intestinal barrier dysfunction with no particularly different effects in tight junction proteins such as ZO-1, claudin-1, and occludin. LPS-triggered inflammatory response was also suppressed by koumine, as evidenced by the downregulated inflammatory factors, including TNF-α, IL-6, IL-1ß, NO, iNOS, and COX-2, which was closely connected with the inhibition of NF-κB pathway for the decrease of phosphorylation of IκBα and NF-κB and nuclear translocation of p-p65. Amount of reactive oxygen species (ROS) and MDA induced by LPS was also reduced by koumine through activation of Nrf2 pathway, and increased in the levels of Nrf2 and HO-1 degradation of keap-1 to promote anti-oxidants, including superoxide dismutase (SOD) and catalase (CAT). To summarize, koumine-reduced the oxidative stress and inflammatory reaction triggered by LPS through regulation of the Nrf2/NF-κB signaling pathway and preventing intestinal barrier dysfunction.

5.
Rapid Commun Mass Spectrom ; : e8715, 2019 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-31886926

RESUMO

RATIONALE: Macleaya microcarpa (Maxim.) Fedde is a genus of Macleaya belonging to papaveraceae family. Benzylisoquinoline alkaloids are considered the main bioactive constituents of M. microcarpa. METHODS: Using HPLC-Q/TOF-MS/MS we identified the benzylisoquinoline alkaloids in the aerial parts of M. microcarpa at early flowering stage. Target profiling and identification of benzylisoquinoline alkloids in the extracted samples from fresh aerial parts of M. microcarpa were exclusively based on a personal accurate mass database of known compounds combined with the mass spectral fragmentation behavior of Macleaya alkaloids. RESULTS: Ninety-seven alkaloids including seven benzyltetrahydroisoquinolines, one aporphine, nine tetraprotoberberines, three protoberberines, two N-methyltetrahydroprotoberberines, four protopines, forty-seven dihydrobenzophenanthridines, and twenty-four benzophenanthridines were identified from the fresh aerial parts of M. microcarpa, and seventy-seven of them were detected for the first time in M. microcarpa. In addition, some of the screened alkaloids were related to the biosynthetic pathways of sanguinarine and chelerythrine. CONCLUSIONS: The integrated method is sensitive and reliable for screening and identifying trace or ultra trace isoquinoline alkaloids and contributed to a better understanding of benzylisoquinoline alkaloids in fresh aerial parts of M. microcarpa.

6.
Huan Jing Ke Xue ; 40(9): 3924-3934, 2019 Sep 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854854

RESUMO

Based on the concentrations of 21 inorganic elements in particulate matter with diameters less than 10 µm (PM10) in 2004, and PM2.5 in 2004 and 2013 of representative road dust in Beijing, the pollution characteristics and potential ecological risks of heavy metals in this dust were analyzed and discussed. The results showed that the six main elements in road dust in Beijing were Si, Ca, Al, Fe, Mg, and K, and the proportions of the total content of the six elements in PM10 in 2004, PM2.5 in 2004, and PM2.5 in 2013 accounted for 96.51%, 96.42%, and 96.53% of the total content of all elements tested, respectively. The elemental enrichment level and the pollution degree and the potential ecological risk of heavy metal in road dust in Beijing in 2004 were PM2.5>PM10. Se, a characteristic element of coal dust, was highly enriched in PM2.5 in 2004, and Cd was high in PM10 and PM2.5 in 2004 with enrichment factors of 1024.03, 68.15, and 871.55, respectively. Co, Zn, Ca, and Cu were significantly enriched in PM10 and PM2.5 in 2004 with enrichment factors of 12.93, 12.33, 8.30, and 8.07 in PM10 and 17.41, 21.80, 12.83, and 19.73 in PM2.5, respectively; Na and Si were not enriched in the road dust. The pollution load index (PLI) of heavy metals was 3.95 in PM10 and 7.71 in PM2.5 in 2004. Owing to the implementation of dust, motor vehicles, and combustion source control measures in Beijing and the relocation of the Shougang corporation, the elemental enrichment level, pollution degree, and potential ecological risk of heavy metals in road dust PM2.5 in 2013 were significantly lower than those in 2004. The enrichment factors of Cd and Se in PM2.5 in 2013 decreased to 98.47 and 0.95, respectively; those of Cu, Ca, and Zn decreased to 11.90, 8.84, and 8.20, respectively; and PLI decreased to 2.56. The results showed that the total potential ecological risk of heavy metals in road dust in Beijing was extremely strong. Heavy metal Cd was the most significant pollution factor and the main potential ecological risk source; its potential ecological risk index (RI) contribution to the total RI of heavy metals was more than 85%. In 2004, the pollution degree of heavy metals in road dust of main roads was significantly higher than that for other road types. The pollution degree of heavy metals in PM10 was main road > expressway entrance to Beijing > secondary main road > ring road; that for PM2.5 was main road > ring road > expressway entrance to Beijing > secondary main road. For PM2.5 in 2013, however, the order was expressway entrance to Beijing > main road > ring road > secondary main road. The pollution degree of heavy metals in road dust of secondary main roads was significantly lower than that for other road types. In 2013, for road dust PM2.5 in Beijing, the correlation of heavy metals Ti, Zn, V, Cr, Cu, Pb, and Ni was significant owing mainly to traffic-related emissions.


Assuntos
Poluentes Atmosféricos , Metais Pesados , Medição de Risco , Pequim , Poeira , Ecologia , Monitoramento Ambiental
7.
Sci Rep ; 9(1): 15756, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673142

RESUMO

Gelsemium elegans is a flowering plant in the Loganiaceae. Because it can promote the growth of pigs and sheep, it is widely used, including in veterinary clinics, but little information is available about its biological effects. Here, we used high-throughput sequencing to characterize the differentially expressed genes (DEGs) in the ileums of pigs between a control group and a group fed Gelsemium elegans for 45 days. We found that Gelsemium elegans affected many inflammatory and immune pathways, including biological processes such as defense responses, inflammation and immune responses. Moreover, this study identified several important genes related to the anti-inflammatory activity of Gelsemium elegans (e.g., CXCL-8, IL1A, and CSF2), which will be beneficial for further study of the pharmacological mechanisms and clinical applications of Gelsemium elegans.

8.
J Pharm Biomed Anal ; 176: 112833, 2019 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-31473492

RESUMO

The multicomponent pharmacokinetic study of herbal medicine is a great challenge due to the low plasma concentrations, large range of concentration scales, lack of authentic standards and uncertain interactions of the components. The aim of this work was to explore the in vivo pharmacokinetics of herbal medicine independently of authentic standards using an integrated analytical strategy. First, ion pairs of multiple components were tuned and selected, and then major parameters were optimized for derivative multiple reaction monitoring (DeMRM) by LC-MS/MS, which was combined with characterization of the chemical profiles of the herbal medicine by LC-QqTOF/MS. Second, different concentrations of herbal extracts were employed instead of authentic standards to construct calibration curves for the semiquantitative determination of multiple components in plasma. Taking Gelsemium elegans as an example, in addition to the fully validated and sufficient methodological results, a total of 27 alkaloid components, major bioactive constituents of Gelsemium elegans, were simultaneously monitored in pig plasma. The concentration-time profiles and pharmacokinetic properties of these 27 components were characterized. The absolute quantification of three components was compared with the results obtained using authentic standards, and the method showed very similar analytical characteristics, such as linearity, precision, accuracy, and the values of the pharmacokinetic parameters Tmax, Vd, Cl and MRT. This analytical strategy was found to be capable of assessing herbal pharmacokinetics independently of specific authentic compounds for each component. This study was the first attempt to systematically reveal the in vivo pharmacokinetics of Gelsemium elegans. This strategy and methodology will find widespread use in the quantitative pharmacokinetic analysis of multiple components independently of standards for herbal medicine, among other applications.

9.
Curr Drug Metab ; 20(7): 583-591, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31203797

RESUMO

BACKGROUND: Gelsemium is a toxic flowering plant of the Gelsemiaceae family. It is used to treat skin diseases in China, and it is an important medicinal and homeopathic plant in North America. Up to now, more than 200 compounds have been isolated and reported from Gelsemium. More than 120 of these are indole alkaloids, including the main components, koumine, gelsemine and humantenmine which produce the pharmacological and toxicological effects of Gelsemium. However, their clinical application their limited by its narrow therapeutic window. Therefore, it is very important to study the metabolism and disposition of indole alkaloids from Gelsemium before their clinical application. This paper reviews all the reports on the metabolism and disposition of alkaloids isolated from Gelsemium at home and abroad. METHODS: The metabolism and disposition of alkaloids from Gelsemium were searched by the Web of Science, NCBI, PubMed and some Chinese literature databases. RESULTS: Only koumine, gelsemine and humantenmine have been reported, and few other alkaloids have been described. These studies indicated that the three indole alkaloids are absorbed rapidly, widely distributed in tissues, extensively metabolized and rapidly eliminated. There are species differences in the metabolism of these alkaloids, which is the reason for the differences in their toxicity in animals and humans. CONCLUSION: This review not only explains the pharmacokinetics of indole alkaloids from Gelsemium but also facilitates further study on their metabolism and mechanism of toxicity.


Assuntos
Alcaloides/metabolismo , Gelsemium/química , Alcaloides Indólicos/metabolismo , Animais , Humanos , Extratos Vegetais/metabolismo
10.
Anal Bioanal Chem ; 411(17): 3857-3870, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31073732

RESUMO

The present paper describes a novel two-dimensional liquid chromatography (2D-LC) system, which is comprised of a first-dimensional ion exchange chromatography (IEX1) column, trap column, and second-dimensional reversed-phase chromatography (RP2) column system. The biological sample is separated by the first-dimensional LC using an IEX column to remove interferences. The analytes are transferred to the trap column after heart-cutting. Then, the analytes are transferred to the second-dimensional LC using an RP2 column for further separation and ultraviolet detection. This 2D-LC system can offer a large injection volume to provide sufficient sensitivity and exhibits a strong capacity for removing interferences. Here, the determination of three monoterpene indole alkaloids (MIAs; gelsemine, koumine, and humantenmine) from Gelsemium in biological matrices (plasma, tissue, and urine) was used this 2D-LC system. After a rapid and easy sample preparation method based on protein precipitation, the sample was injected into the 2D-LC. The method was developed and validated in terms of the selectivity, LOD, LOQ, linearity, precision, accuracy, and stability. The sample preparation time for the three MIAs was 15 min. The LOD for these compounds was 10 ng/mL, which was lower than the developed HPLC methods. The results showed that this method had good quantitation performance and allowed the determination of gelsemine, koumine, and humantenmine in biological matrices. The method is rapid, exhibits high selectivity, has good sensitivity, and is low-cost, thus making it well-suited for application in the pharmaceutical and toxicological analysis of Gelsemium. Graphical abstract.


Assuntos
Alcaloides/análise , Cromatografia por Troca Iônica/instrumentação , Cromatografia de Fase Reversa/instrumentação , Alcaloides Indólicos/análise , Alcaloides/sangue , Alcaloides/normas , Alcaloides/urina , Cromatografia por Troca Iônica/métodos , Cromatografia de Fase Reversa/métodos , Alcaloides Indólicos/sangue , Alcaloides Indólicos/normas , Alcaloides Indólicos/urina , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Espectrofotometria Ultravioleta/métodos
11.
Molecules ; 24(10)2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-31130596

RESUMO

Two optical isomers, +/- gelsemine (1, 2), together with one known compound were isolated from the whole plant of G. elegans. The structures of the separated constituents were elucidated on 1D and 2D (1H-1H COSY, HMBC, HSQC) NMR spectroscopy and high-resolution mass spectrometry (HRMS). The isolated alkaloids were tested in vitro for cytotoxic potential against PC12 cells by the MTT assay. As a result, (+) gelsemine (compound 1) exhibited cytotoxic activity against PC12 cells with an IC50 value of 31.59 µM, while (-) gelsemine (compound 2) was not cytotoxic.


Assuntos
Alcaloides/química , Gelsemium/química , Alcaloides/farmacologia , Animais , Alcaloides Indólicos/química , Alcaloides Indólicos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Células PC12 , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Ratos
12.
Rapid Commun Mass Spectrom ; 33(14): 1179-1184, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30989727

RESUMO

RATIONALE: Gelsemium elegans Benth. belongs to the family Loganiaceae and is widely distributed in northern America, east Asia, and southeast Asia. It has attracted wide attention for its diverse biological effects and complex architectures. Gelsevirine is one of the major components in G. elegans. Compared with other alkaloids from G. elegans, gelsevirine exhibits equally potent anxiolytic effects but with less toxicity. However, the metabolism of gelsevirine has not been clearly elucidated. METHODS: The metabolism of gelsevirine was investigated using liver S9 fractions derived from rat liver homogenates by centrifugation at 9000 g. A rapid and accurate high-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (HPLC/QqTOF-MS) method was applied to characterize the gelsevirine metabolites. RESULTS: We discovered a total number of four metabolites of gelsevirine. The metabolic pathways of gelsevirine consisted of hydrogenation, N-demethylenation and oxidation in rat liver S9. CONCLUSIONS: This is the first study on the metabolism of gelsevirine. We proposed possible metabolic pathways of gelsevirine. These findings may warrant future studies of the in vivo metabolism of gelsemine in animals.

13.
Environ Int ; 126: 560-567, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30852443

RESUMO

Photocatalytic catalysis is widely used for pollutant degradation. Since some pollutants with oxidative nature are readily reduced rather than oxidized and reductive reaction caused by photogenerated electrons is limited in the presence of oxygen, photocatalytic reduction process is more applicable for the degradation of pollutants with oxidative nature than oxidation. In this work, a novel bio-photoelectric reductive degradation system (BPRDS), composed of an electrochemically active bacterium Shewanella oneidensis MR-1 and a visible-light photocatalyst Ag3PO4, was established under anaerobic conditions and its photodegradation performance was evaluated through degrading rhodamine B (RhB), a typical organic pollutant. The as-synthesized Ag3PO4 nanoparticles exhibited absorption in the entire visible spectral range of 400-800 nm. RhB could be degraded in BPRDS with visible light irradiation under anaerobic conditions, but not be decomposed in the absence of Shewanella cells. Block of Mtr respiratory pathway, a transmembrane electron transport chain, resulted in a reduction in degradation rate of RHB in BPRDS. Dose of riboflavin also substantially decreased the RhB degradation. These results suggest that the electrons released by Shewanella were involved in the RhB photodegradation, which was achieved via a stepwise N-deethylation process. In BPRDS, RhB was degraded by photoreduction, rather than photooxidation. This work is useful to develop integrated physico-chemical-microbial systems for pollutant degradation, facilitate better understanding about the biophotoelectric reductive degradation mechanisms and beneficial to their applications for environmental remediation.


Assuntos
Fosfatos/química , Rodaminas/metabolismo , Shewanella/metabolismo , Compostos de Prata/química , Catálise , Luz , Oxirredução , Fosfatos/efeitos da radiação , Fotólise , Compostos de Prata/efeitos da radiação
14.
Proc Natl Acad Sci U S A ; 116(9): 3494-3501, 2019 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-30808744

RESUMO

Rice (Oryza sativa L.) is a chilling-sensitive staple crop that originated in subtropical regions of Asia. Introduction of the chilling tolerance trait enables the expansion of rice cultivation to temperate regions. Here we report the cloning and characterization of HAN1, a quantitative trait locus (QTL) that confers chilling tolerance on temperate japonica rice. HAN1 encodes an oxidase that catalyzes the conversion of biologically active jasmonoyl-L-isoleucine (JA-Ile) to the inactive form 12-hydroxy-JA-Ile (12OH-JA-Ile) and fine-tunes the JA-mediated chilling response. Natural variants in HAN1 diverged between indica and japonica rice during domestication. A specific allele from temperate japonica rice, which gained a putative MYB cis-element in the promoter of HAN1 during the divergence of the two japonica ecotypes, enhances the chilling tolerance of temperate japonica rice and allows it to adapt to a temperate climate. The results of this study extend our understanding of the northward expansion of rice cultivation and provide a target gene for the improvement of chilling tolerance in rice.


Assuntos
Adaptação Fisiológica/genética , Oryza/genética , Proteínas de Plantas/genética , Estresse Fisiológico/genética , Clima , Ciclopentanos/metabolismo , Variação Genética , Isoleucina/análogos & derivados , Isoleucina/genética , Isoleucina/metabolismo , Oryza/crescimento & desenvolvimento , Locos de Características Quantitativas/genética
15.
J Vet Pharmacol Ther ; 42(2): 197-206, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30350369

RESUMO

Sanguinarine (SA) and chelerythrine (CHE) are the main active components of the phytogenic livestock feed additive, Sangrovit®. However, little information is available on the pharmacokinetics of Sangrovit® in poultry. The goal of this work was to study the pharmacokinetics of SA, CHE, and their metabolites, dihydrosanguinarine (DHSA) and dihydrochelerythrine (DHCHE), in 10 healthy female broiler chickens following oral (p.o.) administration of Sangrovit® and intravenous (i.v.) administration of a mixture of SA and CHE. The plasma samples were processed using two different simple protein precipitation methods because the parent drugs and metabolites are stable under different pH conditions. The absorption and metabolism of SA following p.o. administration were fast, with half-life (t1/2 ) values of 1.05 ± 0.18 hr and 0.83 ± 0.10 hr for SA and DHSA, respectively. The maximum concentration (Cmax ) of DHSA (2.49 ± 1.4 µg/L) was higher that of SA (1.89 ± 0.8 µg/L). The area under the concentration vs. time curve (AUC) values for SA and DHSA were 9.92 ± 5.4 and 6.08 ± 3.49 ng/ml hr, respectively. Following i.v. administration, the clearance (CL) of SA was 6.79 ± 0.63 (L·h-1 ·kg-1 ) with a t1/2 of 0.34 ± 0.13 hr. The AUC values for DHSA and DHCHE were 7.48 ± 1.05 and 0.52 ± 0.09 (ng/ml hr), respectively. These data suggested that Sangrovit® had low absorption and bioavailability in broiler chickens. The work reported here provides useful information on the pharmacokinetic behavior of Sangrovit® after p.o. and i.v. administration in broiler chickens, which is important for the evaluation of its use in poultry.


Assuntos
Benzofenantridinas/farmacocinética , Galinhas/metabolismo , Isoquinolinas/farmacocinética , Administração Oral , Animais , Benzofenantridinas/administração & dosagem , Benzofenantridinas/sangue , Galinhas/sangue , Cromatografia Líquida de Alta Pressão/veterinária , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacocinética , Feminino , Meia-Vida , Injeções Intravenosas/veterinária , Isoquinolinas/administração & dosagem , Isoquinolinas/sangue , Espectrometria de Massas/veterinária
16.
Rapid Commun Mass Spectrom ; 32(23): 2047-2054, 2018 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-30252168

RESUMO

RATIONALE: N-Methylcanadine and N-methylstylopine are two types of isoquinoline alkaloids which are considered to be the main medicinally active constituents of the genus Papaveraceae. However, to date, no metabolism studies of N-methylcanadine and N-methylstylopine have been reported. Therefore, the purpose of the present study was to investigate the in vitro metabolism of these two alkaloids in rat liver S9. METHODS: N-Methylcanadine or N-methylstylopine was incubated with rat liver S9 for 1 h, and then the incubation mixture was processed with 15% trichloroacetic acid. High-performance liquid chromatography with quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS) as a reliable analytical method was used. The structural characterization of these metabolites was performed by the combination of the accurate MS/MS spectra and the known elemental composition. RESULTS: As a result, a total of four metabolites of N-methylcanadine and five metabolites of N-methylstylopine in rat liver S9 were tentatively identified. The cleavage of the methylenedioxy group of the drugs was the main metabolic pathway of N-methylcanadine and N-methylstylopine. CONCLUSIONS: The present study is the first in vitro metabolic investigation of N-methylcanadine and N-methylstylopine in rat liver S9 using a reliable HPLC/QqTOF-MS method. The metabolic pathways of N-methylcanadine and N-methylstylopine are tentatively proposed. This work lays the foundation for the in vivo metabolism of the two compounds in animals.


Assuntos
Alcaloides/química , Alcaloides de Berberina/química , Cromatografia Líquida de Alta Pressão/métodos , Microssomos Hepáticos/química , Papaveraceae/química , Extratos Vegetais/química , Espectrometria de Massas em Tandem/métodos , Alcaloides/metabolismo , Animais , Alcaloides de Berberina/metabolismo , Masculino , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Extratos Vegetais/metabolismo , Ratos , Ratos Sprague-Dawley
17.
Rapid Commun Mass Spectrom ; 32(17): 1540-1548, 2018 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-29935083

RESUMO

RATIONALE: Tetrahydroberberine (THB), tetrahydrocoptisine (THCP) and tetrahydrocolumbamine (THCB) belong to the tetrahydroprotoberberine (THPB) alkaloids. Most of them have been extensively studied because of their pharmacological activities such as anti-hypertension, anti-arrhythmia, antimicrobial activity and antioxidant. However, limited information on the pharmacokinetics and metabolism of the three alkaloids has been reported. The purpose of this study was to investigate the in vitro metabolism of THB, THCP and THCB in rat liver S9 by using a rapid and accurate high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (HPLC/QqTOF-MS) method. METHODS: The incubation mixture was processed with 15% trichloroacetic acid. Chromatographic separation of the three THPB alkaloids and their metabolites was achieved by HPLC/QqTOF-MS and accurate mass measurements of metabolites were automatically performed through data-dependent acquisition in only a 30-min analysis. The detailed structural elucidations of these metabolites were performed by comparing the changes in their accurate molecular masses, elemental compositions and product ions with those of the parent drug. RESULTS: Five, five and four metabolites of THB, THCP and THCB were identified in rat liver S9, respectively. The results show that O-demethylenation of the 9,10-vicinal methoxyl group was the main metabolic pathway of THB and THCB and that demethylenation of the two methylenedioxy groups was the main metabolic pathway of THCP. In addition, minor oxidation and methylation reactions could occur for these alkaloids in rat liver S9. CONCLUSIONS: This was the first investigation of the in vitro metabolism of THB, THCP and THCB in rat liver S9 by using a sensitive and accurate HPLC/QqTOF-MS method. The tentatively proposed metabolic pathways of the three alkaloids will provide a basis for further studies of the in vivo metabolism of the three compounds in animals and humans.


Assuntos
Alcaloides de Berberina/química , Alcaloides de Berberina/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas/métodos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Animais , Humanos , Masculino , Estrutura Molecular , Ratos
18.
Artigo em Inglês | MEDLINE | ID: mdl-29406028

RESUMO

Three monomers of G. elegans indole alkaloids (gelsemine, koumine and humantenmine) were simultaneously detected in porcine plasma for the first time with the development and validation of a sensitive and reliable LC-ESI-MS/MS method. Using a gradient mobile phase at a constant flow rate of 0.2 mL/min via electrospray ionization (positive ion mode) in a multiple reaction monitoring (MRM) scan, gelsemine, koumine and humantenmine were eluted, separated and detected at an appropriate retention time. The porcine plasma was prepared using protein precipitation with 1% formic acid-acetonitrile: methanol (2:1, v/v). Using matrix-matched calibration curves and weighted least squares linear regression, a good linearity (r2 > 0.99) was achieved with a concentration range of 0.1-200 µg/L for gelsemine, koumine and humantenmine; estimated LOD and LOQ values were 0.10 µg/L and 0.2 µg/L, respectively. The mean of the recoveries was in the range of 82.68-100.35% of porcine plasma at four different levels, and the intra-day and inter-day precision (CV) were lower than 15% with a range of 2.46-8.76% and 2.73-10.83%, respectively. The proposed method has proved to be suitable for accurate, quantitative determination of gelsemine, koumine and humantenmine in porcine plasma.


Assuntos
Alcaloides/sangue , Cromatografia Líquida/métodos , Alcaloides Indólicos/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Suínos
19.
Sci Rep ; 8(1): 537, 2018 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-29323165

RESUMO

In this study, the biotransformation in the plasma, urine and feces of rats following oral administration of protopine (PRO) and allocryptopine (ALL)were explored using HPLC-QqTOF MS. An HPLC-MS/MS method for the determination of tissues was developed and applied to the tissue distribution study in rats following intragastric administration of Plume Poppy Total Alkaloid for 3 weeks. A total of ten PRO metabolites and ten ALL metabolites were characterized in rats in vivo. Among these metabolites, six PRO metabolites and five ALL metabolites were reported for the first time. The predicated metabolic pathways including ring cleavage, demethylation following ring cleavage, and glucuronidation were proposed. The low-concentration residue of PRO and ALL in various tissues was detected at 24 h and 48 h after dosing, which indicated that both compounds could be widely distributed in tissues and exist as low levels of residue. The activities of erythromycin N-demethylase, aminopyrine N-demethylase and NAD (P)H quinone oxidoreductase in female rats can be induced post-dose, but these activities were inhibited in male rats. The proposed biotransformation and residues of PRO and ALL and their effects on enzymes may provide a basis for clarifying the metabolism and interpreting pharmacokinetics.


Assuntos
Benzofenantridinas/farmacocinética , Alcaloides de Berberina/farmacocinética , Fígado/metabolismo , Aminopirina N-Desmetilase/metabolismo , Animais , Benzofenantridinas/sangue , Benzofenantridinas/urina , Alcaloides de Berberina/sangue , Alcaloides de Berberina/urina , Citocromo P-450 CYP3A/metabolismo , Feminino , Inativação Metabólica , Fígado/enzimologia , Masculino , Papaveraceae/química , Quinona Redutases/metabolismo , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
20.
Rapid Commun Mass Spectrom ; 32(1): 19-22, 2018 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-29027298

RESUMO

RATIONALE: Gelsemine has been extensively studied because of its anti-tumor, immunomodulatory, insecticidal itching and other significant effects. However, limited information on the pharmacokinetics and metabolism of gelsemine has been reported. Therefore, the purpose of the present study was to investigate the in vitro metabolism of gelsemine in rat liver S9 by using rapid and accurate high-performance liquid chromatography/ quadrupole-time-of-flight mass spectrometry (HPLC/QqTOF-MS). METHODS: The incubation mixture was processed with 15% trichloroacetic acid. Multiple scans of gelsemine metabolites and accurate mass measurements were automatically performed simultaneously through data-dependent acquisition in only 30 min. The structural elucidations of these metabolites were performed by comparing their changes in accurate molecular masses and product ions with those of the parent drug. RESULTS: Five metabolites of gelsemine were identified in rat liver S9. Of these, four metabolites of gelsemine were identified for the first time. The present results showed that the metabolic pathways of gelsemine are oxidation, demethylation, and dehydrogenation in rat liver S9. CONCLUSIONS: In this study, metabolites of gelsemine in liver S9 were identified and elucidated firstly using the HPLC/QqTOF-MS method. The proposed metabolic pathways of gelsemine in liver S9 will provide a basis for further studies of the in vivo metabolism of gelsemine in animals and humans.


Assuntos
Alcaloides/metabolismo , Gelsemium/química , Fígado/metabolismo , Extratos Vegetais/metabolismo , Alcaloides/química , Animais , Cromatografia Líquida de Alta Pressão , Fígado/química , Espectrometria de Massas , Estrutura Molecular , Extratos Vegetais/química , Ratos
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