Pharmacokinetics of Five Alkaloids and their Metabolites in Normal and Diabetic Rats after Oral Administration of Rhizoma coptidis

Planta Medica ◽  
2021 ◽  
Author(s):  
Xinchi Feng ◽  
Kun Wang ◽  
Shijie Cao ◽  
Liqin Ding ◽  
Feng Qiu
Keyword(s):  
Oral Administration ◽  
Diabetic Rats ◽  
Pharmacokinetic Studies ◽  
Rhizoma Coptidis ◽  
Material Basis ◽  
Diabetic Model ◽  
Long Time ◽  
Treatment Of Diabetes ◽  
Phase Ii Metabolites

AbstractRhizoma coptidis has been clinically used for a long time for the treatment of various diseases in China, such as hypertension, diabetes, and inflammation. Previous studies have shown that alkaloid components of Rhizoma coptidis extract could be extensively metabolized and the metabolites were also considered to be the therapeutic material basis. However, until now, pharmacokinetic studies of the in vivo metabolites have not been revealed yet. The aim of the present study was to characterize the pharmacokinetics and excretions of five main alkaloids (berberine, jatrorrhizine, palmatine, epiberberine, and coptisine) and their seven metabolites (berberrubine, demethyleneberberine, jatrorrhizine-3-O-β-D-glucuronide, thalifendine-10-O-β-D-glucuronide, berberrubine-9-O-β-D-glucuronide, demethyleneberberine-2-O-sulfate, and demethyleneberberine-2-O-β-D-glucuronide) in rats after oral administration of Rhizoma coptidis extract. Meanwhile, comparative pharmacokinetics and excretions of these analytes in diabetic model rats were also investigated, since Rhizoma coptidis is widely used for the treatment of diabetes. Our results showed that the in vivo existing forms of alkaloid components were phase II metabolites, highlighting the glucuronidation metabolic pathway. In diabetic model rats, the utilization of Rhizoma coptidis alkaloids was significantly increased and the biotransformation of berberine into berberrubine was significantly inhibited.

scholarly journals Design and Characterization of Combinational Domperidone-Famotidine Floating Drug Delivery System - In vitro and In vivo studies

2021 ◽  
Vol 62 (2) ◽  
pp. 144-162
Author(s):  
Mounika Chidurala ◽  
Raveendra Reddy J
Keyword(s):  
Drug Release ◽  
Oral Administration ◽  
Quality By Design ◽  
Release Kinetics ◽  
Cost Effective ◽  
Fickian Diffusion ◽  
In Vivo Studies ◽  
Pharmacokinetic Studies

Introduction: The drawbacks assosiated with oral administration of drugscan be controlled or minimized by gastro retentive formulations that remain buoyant within the stomach for an extended time by providing prolonged gastric retention and releasethe drug in an exceedingly extended manner thereby improving bioavailability. The current research was to develop and optimize Domperidone and Famotidine floating tablets with extended release by Quality by Design approach. Method: Based on QTPP (Quality Target Product Profile), CQAs (Critical Quality Attributes)wereidentified. Risk analysis by the evaluation of formulation and process parameters showed that optimizing the levels of polymers could reduce high risk to achieve the target profile. A 23factor experimental design with midpoints was selected for statistical analysis and optimization. Results: HPMC K100 and Carbopol 934P had a positive effect while ethyl cellulose demonstrated a negative effect on the selected responses. Drug release kinetics followed the first-order release with Higuchi diffusion and Fickian diffusion. Optimized formula satisfying all the required parameters was selected and evaluated. The predicted response values were in close agreement with experimental response values. Abdominal X-ray imaging after oral administration of the tablets on a healthy rabbit’s stomach confirmed the extended floating behavior with shorter lag time. In vivo, pharmacokinetic studies in rabbits revealed that the optimized formulation exhibited prolonged drug release with enhanced Cmax, tmax, AUCo-t, and t1/2 of an optimized product when compared to the marketed product. Conclusions: It has been concluded that the application of Quality by Design in the formulation and optimization reduced the number of trials to produce a cost-effective formula.

scholarly journals An LC-MS/MS Method for Simultaneous Determination of the Toxic and Active Components of Cortex Periplocae in Rat Plasma and Application to a Pharmacokinetic Study

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Zhen Li ◽  
Yang Li ◽  
Jin Li ◽  
Rui Liu ◽  
Jia Hao ◽  
...  
Keyword(s):  
Oral Administration ◽  
Multiple Reaction Monitoring ◽  
Gradient Elution ◽  
Rat Plasma ◽  
Pharmacokinetic Studies ◽  
Simple Liquid ◽  
Active Components ◽  
Limit Of Quantification ◽  
Liquid Chromatography Tandem Mass

A sensitive and simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine the toxic and other active components including isovanillin, scopoletin, periplocin, periplogenin, and periplocymarin after oral administration of cortex periplocae extract to rats. Plasma samples were prepared by protein precipitation with methanol. All compounds were separated on a C18 column with gradient elution using acetonitrile and formic acid aqueous solution (0.1%, v/v) as the mobile phase at a flow rate of 0.3 mL/min. The detection of all compounds was accomplished by multiple-reaction monitoring (MRM) in the positive electrospray ionization mode. The LC-MS/MS method exhibited good linearity for five analytes. The lower limit of quantification (LLOQ) was 0.48 ng/mL for scopoletin, periplogenin, and periplocymarin; 2.4 ng/mL for isovanillin and periplocin. The extraction recoveries of all compounds were more than 90% and the RSDs were below 10%. It was found that the absorption of scopoletin and periplocin was rapid in vivo after oral administration of cortex periplocae extract. Furthermore, periplocymarin possessed abundant plasma exposure. The results demonstrated that the validated method was efficiently applied for the pharmacokinetic studies of isovanillin, scopoletin, periplocin, periplogenin, and periplocymarin after oral administration of cortex periplocae extract.

Influence of Loranthus micranthus on hepatic and renal antioxidant status and impaired glycolytic flux in streptozotocin-induced diabetic rats

2018 ◽  
Vol 29 (5) ◽  
pp. 447-461 ◽  
Author(s):  
Azubuike P. Ebokaiwe ◽  
Omamuyovwi M. Ijomone ◽  
Oscar Edeh ◽  
Ifebunachi Oteh ◽  
David E. Ebuka
Keyword(s):  
Glucose Metabolism ◽  
Antioxidant Status ◽  
Leaf Extract ◽  
Diabetic Rats ◽  
Glycolytic Flux ◽  
Traditional Use ◽  
Metabolism Enzymes ◽  
Liver And Kidney ◽  
Treatment Of Diabetes

Abstract Background The use of Loranthus micranthus in folklore medicine for treatment of diabetes and its associated complications is a common practice around the world. The present study investigated this traditional affirmation by in vivo investigation into the effect of L. micranthus leaf extract on hepatic and renal, oxidative status and glucose metabolism in streptozotocin (STZ)-induced diabetic rats. Methods Diabetes mellitus was induced in adult male Wistar rats by intraperitoneal injection of STZ (60 mg/kg). The diabetic rats were thereafter treated orally once per day with 5 mg/kg gilbenclamide or L. micranthus leaf extract (100 or 200 mg/kg) and monitored for 14 days. Clinical observations, plasma biochemistry, hormonal profile, oxidative stress parameters, glucose metabolism enzymes and histopathologic examination of the liver and kidney were evaluated to monitor treatment-related effects of L. micranthus leaf extract in STZ-induced diabetic rats. Results Loranthus micranthus leaf extract administration significantly ameliorated hyperglycemia-mediated damage by decreasing the blood glucose level (45.9% and 84.7% on days 7 and 14 posttreatment, respectively), enhancing the antioxidant status, inhibiting lipid peroxidation and improving the architecture of the liver and kidney in STZ-induced diabetic rats. Furthermore, intervention of L. micranthus leaf extract restored the liver and kidney function biomarkers and increased the plasma levels of triiodothyronine and thyroxine to normal control in STZ-induced diabetic rats. Conclusions The findings from this investigation provide credible scientific support for the traditional use of L. micranthus leaf extract in the treatment of diabetes and its associated complications.

scholarly journals Comparative evaluation of anti-diabetic activity of fresh juice and ethanolic extract of Sunderban mangrove Rhizophora mucronata Lam. leaves in animal model

2017 ◽  
Vol 6 (9) ◽  
pp. 2193
Author(s):  
Anjan Adhikari ◽  
Moumita Ray ◽  
Tapas K. Sur ◽  
Sharmistha Biswas ◽  
Anup K. Das
Keyword(s):  
Comparative Analysis ◽  
Folk Medicine ◽  
Ethanolic Extract ◽  
Ethanol Extract ◽  
Diabetic Rats ◽  
Lipid Lowering ◽  
Rhizophora Mucronata ◽  
Potent Effect ◽  
Diabetic Model ◽  
Treatment Of Diabetes

Background: Mangrove flora possess compounds with potential medicinal values with unique bioactive components. Traditionally Rhizophora mucronata, a mangrove has been used extensively for the treatment of diabetes. Studies revealed that, the leaves of Rhizophora (Bhora) had promising anti-diabetic action in rat model.Methods: A comparative analysis of the anti-diabetic action of fresh juice and ethanolic extract of Rhizophora mucronata leaves was carried out in Streptozotocin induced diabetic model and the different biochemical parameters were evaluated.Results: Present research explored a comparative analysis of the anti-diabetic action of fresh juice and ethanolic extract of leaves of Rhizophora mucronata Lam. in Streptozotocin induced diabetic model. The ethanolic extract showed more potent effect in lowering the elevated blood sugar in the diabetic rats, 200mg/kg was the most effective dose for both the extracts. The ethanol extract was more beneficial having potent lipid lowering action along with anti-hyperglycemic property.Conclusions: This supports the scientific validation for using Rhizophora mucronata leaves in the treatment of diabetes as traditional folk medicine. Identification of the bioactive molecule is under process.

scholarly journals Profiling and Pharmacokinetic Studies of Alkaloids in Rats After Oral Administration of Zanthoxylum nitidum Decoction by UPLC-Q-TOF-MS/MS and HPLC-MS/MS

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 585 ◽  
Author(s):  
Aihua Huang ◽  
Yuguang Chi ◽  
Jiawei Liu ◽  
Mincun Wang ◽  
Jialiang Qin ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Liquid Chromatography ◽  
Oral Administration ◽  
High Performance ◽  
Ultra Performance Liquid Chromatography ◽  
Rat Plasma ◽  
Pharmacokinetic Studies ◽  
Flight Mass Spectrometry ◽  
Zanthoxylum Nitidum

Zanthoxylum nitidum (Roxb.) DC (Rutaceae), called as “liangmianzhen” in China, is well known for its anti-inflammation and analgesic effect. Alkaloids are its main active constituents. However, little has been known about the absorption of main alkaloids in vivo. In this study, an ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry was employed for identification of absorbed alkaloids in rats after oral administration of Z. nitidum decoction. By analyzing the fragmentation patterns, a total of nineteen alkaloids were exactly or tentatively identified in rat plasma after treatment, of which magnoflorine, α-allocryptopine, and skimmianine are dominant. Moreover, a high performance liquid chromatography coupled mass spectrometry method was developed for simultaneous quantification of magnoflorine, α-allocryptopine, and skimmianine, and successfully applied to pharmacokinetic study in rats after oral administration of Z. nitidum decoction. The research would contribute to comprehensive understanding of the material basis and function mechanism of Z. nitidum decoction.

scholarly journals Pharmacokinetic Comparison of 20(R)- and 20(S)-Ginsenoside Rh1 and 20(R)- and 20(S)-Ginsenoside Rg3 in Rat Plasma following Oral Administration of Radix Ginseng Rubra and Sheng-Mai-San Extracts

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaomei Fan ◽  
Yan Xu ◽  
Danni Zhu ◽  
Yibing Ji
Keyword(s):  
Oral Administration ◽  
Rat Plasma ◽  
Pharmacokinetic Parameters ◽  
Spectrometric Method ◽  
Pharmacokinetic Studies ◽  
Mass Spectrometric Method ◽  
Ginsenoside Rg3 ◽  
Radix Ginseng

Ginsenosides Rh1 and Rg3, as the main bioactive components from Ginseng, are effective for prevention and treatment of cardiovascular diseases. Sheng-Mai-San (SMS), a classical complex prescription of traditional Chinese medicines, is composed of Radix Ginseng Rubra, Fructus Schisandrae, and Radix Ophiopogonis. In this research, a sensitive and specific liquid chromatography-mass spectrometric method was developed and validated for stereoselective determination and pharmacokinetic studies of 20(R)- and 20(S)-ginsenoside Rh1 and 20(R)- and 20(S)-ginsenoside Rg3 epimers in rat plasma after oral administration of Radix Ginseng Rubra or SMS extracts. The main pharmacokinetic parameters including Tmax, Cmax, t1/2, and AUC were calculated by noncompartment model. Compared with Radix Ginseng Rubra, SMS could significantly increase the content of ginsenosides Rh1 and Rg3 in the decocting process. Ginsenosides Rh1 and Rg3 following SMS treatment displayed higher Cmax, AUC(0–t), and AUC0–∞ and longer t1/2 and tmax except for 20(R)-Rh1 in rat plasma. The results indicated SMS compound compatibility could influence the dissolution in vitro and the pharmacokinetic behaviors in vivo of ginsenosides Rh1 and Rg3, suggesting pharmacokinetic drug-drug interactions between ginsenosides Rh1 and Rg3 and other ingredients from Fructus Schisandrae and Radix Ophiopogonis. This study would provide valuable information for drug development and clinical application of SMS.

scholarly journals Identification and Pharmacokinetic Studies on Complanatuside and Its Major Metabolites in Rats by UHPLC-Q-TOF-MS/MS and LC-MS/MS

Molecules ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 71 ◽  
Author(s):  
Yu-Feng Yao ◽  
Chao-Zhan Lin ◽  
Fang-Le Liu ◽  
Run-Jing Zhang ◽  
Qiu-Yu Zhang ◽  
...  
Keyword(s):  
Oral Administration ◽  
Degradation Products ◽  
Plasma Concentrations ◽  
Rat Plasma ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Studies ◽  
Maximum Plasma ◽  
Time Curve ◽  
Tof Ms

The metabolic and pharmacokinetic studies on complanatuside, a quality marker of a Chinese materia medicatonic, Semen Astragali Complanati, were carried out. The UHPLC-Q-TOF/MS (ultra-high performance liquid chromatography coupled with electrospray ionization tandem quadrupole-time-of-flight mass spectrometry) method was applied to identify the metabolites of complanatuside in rat plasma, bile, stool, and urine after oral administration at the dosage of 72 mg/kg. Up to 34 metabolites (parent, 2 metabolites of the parent drug, and 31 metabolites of the degradation products) were observed, including processes of demethylation, hydroxylation, glucuronidation, sulfonation, and dehydration. The results indicated glucuronidation and sulfonation as major metabolic pathways of complanatuside in vivo. Meanwhile, a HPLC-MS method to quantify complanatuside and its two major metabolites—rhamnocitrin 3-O-β-glc and rhamnocitrin—in rat plasma for the pharmacokinetic analysis was developed and validated. The Tmax (time to reach the maximum drug concentration) of the above three compounds were 1 h, 3 h, and 5.3 h, respectively, while the Cmax (maximum plasma concentrations)were 119.15 ng/mL, 111.64 ng/mL, and 1122.18 ng/mL, and AUC(0-t) (area under the plasma concentration-time curve) was 143.52 µg/L·h, 381.73 µg/L·h, and 6540.14 µg/L·h, accordingly. The pharmacokinetic characteristics of complanatuside and its two metabolites suggested that complanatuside rapidly metabolized in vivo, while its metabolites—rhamnocitrin—was the main existent form in rat plasma after oral administration. The results of intracorporal processes, existing forms, and pharmacokinetic characteristics of complanatuside in rats supported its low bioavailability.

scholarly journals Comparative Studies on Multi-Component Pharmacokinetics of Polygonum multiflorum Thunb Extract After Oral Administration in Different Rat Models

2021 ◽  
Vol 12 ◽  
Author(s):  
Ninghui Ma ◽  
Yong Zhang ◽  
Liyan Sun ◽  
Yuan Zhao ◽  
Yue Ding ◽  
...  
Keyword(s):  
Phase Ii ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Polygonum Multiflorum ◽  
Liquid Chromatography Tandem Mass ◽  
Aloe Emodin ◽  
Main Basis ◽  
Phase Ii Metabolites

The clinical use of Polygonum multiflorum Thunb (PM) has been restricted or banned in many countries, due to its hepatotoxic adverse effects. Its toxicity research has become a hot topic. So far, the pharmacokinetic studies of PM, focusing on prototype compounds such as 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (TSG), emodin, and physcion, have been considered the main basis of pharmacodynamic material or of toxic effect. However, pharmacokinetic studies of its phase II metabolites have not yet been reported, mainly because the quantifications of such metabolites are difficult to do without the reference substance. In addition, pharmacokinetic studies on different pathological models treated with PM have also not been reported. On the other hand, toxic effects of PM have been reported in patients diagnosed with different liver pathologies. In the present work, a simultaneous quantitation method for eight prototypes components of PM and their five phase II metabolites has been performed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and used for the pharmacokinetic study of PM in two different liver pathological models in rats (normal, alpha-naphthylisothiocyanate (ANIT), and carbon tetrachloride (CCl4)). The results showed that the main blood-entering components of PM are TSG, emodin, physcion, emodin-8-O-β⁃D⁃glucoside (E-Glu), physcion-8-O-β⁃D⁃glucoside (P-Glu), aloe-emodin, gallic acid, resveratrol and catechin, among which TSG, emodin, and catechin were primary metabolized in phase II, while resveratrol was converted to all phase II metabolites, and the others were metabolized as drug prototypes. Meanwhile, their pharmacokinetic parameters in the different models also exhibited significant differences. For instance, the AUC (0-∞) values of the TSG prototype and its phase II metabolites were higher in the ANIT group, followed by CCl4 group and the normal group, while the AUC (0-∞) values of the emodin prototype and its phase II metabolites were higher in the CCl4 group. To further illustrate the reasons for the pharmacokinetic differences, bilirubin metabolizing enzymes and transporters in the liver were measured, and the correlations with the AUC of the main compounds were analyzed. TSG and aloe-emodin have significant negative correlations with UGT1A1, BSEP, OATP1A4, OCT1, NTCP, MRP2 and MDR1 (p < 0.01). These data suggest that when the expression of metabolic enzymes and transporters in the liver is inhibited, the exposure levels of some components of PM might be promoted in vivo.

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