scholarly journals A Herb-drug interaction study: Screen the inhibitory effects of Insulin plant extract on rat liver CYP2D6 isoenzyme upon concurrent administration of Aripiprazole

2020 ◽  
Vol 10 (3) ◽  
pp. 15-23
Author(s):  
Harshita Gupta ◽  
Bhagyashree Kamble
Keyword(s):  
Rat Liver ◽  
Plant Extract ◽  
Liver Microsomes ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Diabetic Patients ◽  
Concurrent Administration ◽  
High Blood Glucose ◽  
Successive Extraction

Aripiprazole belongs to the atypical antipsychotic category of drug. Cytochrome2D6 (CYP2D6) is one of the prominent enzymes that play a key role in the metabolism of Aripiprazole and further formation of an active metabolite, Dehydroaripiprazole takes place. Patients under the treatment with this potent moiety have been reported with the high blood glucose level as a side effect. In addition to this, literature suggests that the leaves of Insulin plant (Costus igneus) are usually administered by diabetic patients (2-3 times) to manage the sugar level without concerning to the physicians. There might be probability while concurrent administration of (Aripiprazole and Insulin plant leaves), leaves inhibit the enzyme and ultimately Dehydroaripiprazole exhibit poor pharmacological action. Hence, the present work was done to investigate the inhibitory effect of Insulin plant extract (IPE) on CYP2D6, with the co-administration of Aripiprazole (to examine the changes in a metabolite of Aripiprazole). In order to carry out this protocol firstly, IPE was prepared by the successive extraction method. Methanolic extract of Insulin plant was found enriched with the Quercetin, which was used as a marker to carry out this study. Presence of Quercetin was confirmed with the Ultra-violet spectroscopy (UV) and High-performance liquid chromatography (HPLC) analytical methods. Characterization of Aripiprazole was done with the help of different analytical tools such as: HPLC, melting point, and UV. Aripiprazole alone and with the several dilutions of IPE were incubated using isolated rat liver microsome (RLM) and analyzed using HPLC. HPLC data demonstrated that the, mixture of IPE+Aripiprazole (herb and drug in liver microsomes), in comparison to Aripiprazole+RLM (alone drug in liver microsomes) has not shown any significant inhibition of the enzyme, and inhibitory concentration (IC50) value found to be 4.49µg/ml. Therefore this study concluded that IPE has shown safe results even at the highest clinical dose after oral administration i.e., 20-1000µg/ml and did not show any significant CYP2D6 inhibition. Nevertheless, to confirm these observations, inclusion of in vivo studies will be advantageous. As per our knowledge, this is the first attempt made on the detection of Herb- Drug interactions (HDI’S) between Insulin plant and Aripiprazole.  

ANTITUMOR EFFECT OF COLLOIDAL SILVER BISILICATE IN EXPERIMENTAL IN VITRO AND IN VIVO STUDIES

2019 ◽  
Vol 65 (5) ◽  
pp. 760-765
Author(s):  
Margarita Tyndyk ◽  
Irina Popovich ◽  
A. Malek ◽  
R. Samsonov ◽  
N. Germanov ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Human Tumor ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
Ehrlich Carcinoma ◽  
In Vivo Experiments

The paper presents the results of the research on the antitumor activity of a new drug - atomic clusters of silver (ACS), the colloidal solution of nanostructured silver bisilicate Ag6Si2O7 with particles size of 1-2 nm in deionized water. In vitro studies to evaluate the effect of various ACS concentrations in human tumor cells cultures (breast cancer, colon carcinoma and prostate cancer) were conducted. The highest antitumor activity of ACS was observed in dilutions from 2.7 mg/l to 5.1 mg/l, resulting in the death of tumor cells in all studied cell cultures. In vivo experiments on transplanted Ehrlich carcinoma model in mice consuming 0.75 mg/kg ACS with drinking water revealed significant inhibition of tumor growth since the 14th day of experiment (maximally by 52% on the 28th day, p < 0.05) in comparison with control. Subcutaneous injections of 2.5 mg/kg ACS inhibited Ehrlich's tumor growth on the 7th and 10th days of the experiment (p < 0.05) as compared to control.

scholarly journals The Antitumor Activity of Sodium Selenite Alone and in Combination with Gemcitabine in Pancreatic Cancer: An In Vitro and In Vivo Study

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3169
Author(s):  
Kevin Doello ◽  
Cristina Mesas ◽  
Francisco Quiñonero ◽  
Gloria Perazzoli ◽  
Laura Cabeza ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Sodium Selenite ◽  
Molecular Mechanisms ◽  
Combined Therapy ◽  
Significant Inhibition ◽  
In Vivo Studies ◽  
C57bl Mice ◽  
Migration Capacity

Sodium selenite acts by depleting enzymes that protect against cellular oxidative stress. To determine its effect alone or in combination with gemcitabine (GMZ) in pancreatic cancer, we used PANC-1 and Pan02 cell lines and C57BL mice bearing a Pan02-generated tumor. Our results demonstrated a significant inhibition of pancreatic cancer cell viability with the use of sodium selenite alone and a synergistic effect when associated with GMZ. The molecular mechanisms of the antitumor effect of sodium selenite alone involved apoptosis-inducing factor (AIF) and the expression of phospho-p38 in the combined therapy. In addition, sodium selenite alone and in association with GMZ significantly decreased the migration capacity and colony-forming ability, reduced tumor activity in multicellular tumor spheroids (MTS) and decreased sphere formation of cancer stem cells. In vivo studies demonstrated that combined therapy not only inhibited tumor growth (65%) compared to the untreated group but also relative to sodium selenite or GMZ used as monotherapy (up to 40%), increasing mice survival. These results were supported by the analysis of C57BL/6 albino mice bearing a Pan02-generated tumor, using the IVIS system. In conclusion, our results showed that sodium selenite is a potential agent for the improvement in the treatment of pancreatic cancer and should be considered for future human clinical trials.

In Vitro Metabolism of E2, G2: Novel Bile Acid-Coupling Camptothecin Analogues, in Rat Liver Microsomes

2021 ◽  
Vol 16 ◽  
Author(s):  
Xiangli Zhang ◽  
Qin Shen ◽  
Yi Wang ◽  
Leilei Zhou ◽  
Qi Weng ◽  
...  
Keyword(s):  
Bile Acid ◽  
Phase I ◽  
Rat Liver ◽  
Deoxycholic Acid ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
Rat Liver Microsomes ◽  
Camptothecin Analogues

Background: E2 (Camptothecin - 20 (S) - O- glycine - deoxycholic acid), and G2 (Camptothecin - 20 (S) - O - acetate - deoxycholic acid) are two novel bile acid-derived camptothecin analogues by introducing deoxycholic acid in 20-position of CPT(camptothecin) with greater anticancer activity and lower systematic toxicity in vivo. Objective: We aimed to investigate the metabolism of E2 and G2 by Rat Liver Microsomes (RLM). Methods: Phase Ⅰ and Phase Ⅱ metabolism of E2 and G2 in rat liver microsomes were performed respectively, and the mixed incubation of phase I and phase Ⅱ metabolism of E2 and G2 was also processed. Metabolites were identified by liquid chromatographic/mass spectrometry. Results: The results showed that phase I metabolism was the major biotransformation route for both E2 and G2. The isoenzyme involved in their metabolism had some difference. The intrinsic clearance of G2 was 174.7mL/min. mg protein, more than three times of that of E2 (51.3 mL/min . mg protein), indicating a greater metabolism stability of E2. 10 metabolites of E2 and 14 metabolites of G2 were detected, including phase I metabolites (mainly via hydroxylations and hydrolysis) and their further glucuronidation products. Conclusion: These findings suggested that E2 and G2 have similar biotransformation pathways except some difference in the hydrolysis ability of the ester bond and amino bond from the parent compounds, which may result in the diversity of their metabolism stability and responsible CYPs(Cytochrome P450 proteins).

Anti-Diabetic Retinopathy Potential of Noni: The beneficial effect and possible mechanism

2020 ◽  
Vol 3 (1) ◽  
pp. 01-21
Author(s):  
Faisal Ali
Keyword(s):  
Diabetic Retinopathy ◽  
Prolonged Exposure ◽  
Morinda Citrifolia ◽  
In Vivo Studies ◽  
Laboratory Research ◽  
Tropical Region ◽  
Bioactive Substances ◽  
High Blood Glucose

Noni (Morinda citrifolia L.) is being evaluated in laboratory research for its benefits as an antioxidant and immunity booster, as well as for its properties to prevent tumors and cure diabetes. The vast spread of Noni in tropical region of the globe, from America reaching to Africa and Southeast Asia, contributed in enhancing its usage and potency due to the diversity in harvest zone. Noni parts comprise fruits, seeds, leaves, and flowers are being used for individual nutritional and therapeutical values. Nevertheless, the fruit is widely characterized to contain the most valuable bioactive substances. On the other hand, diabetic retinopathy (DR) is a microvascular disorder impacting the small blood vessels in the retina, which includes microaneurysms, retinal hemorrhages, and hard exudates results from prolonged exposure to high blood glucose levels. The anti-diabetes effect of Noni extract and juice has been examined but the beneficial role of Noni and its potential mechanisms against the development of diabetic retinopathy phenotype is still ambiguous. This review, therefore, will discusses in details the pharmacological actions of M. citrifolia fruit, along with their isolated phytochemical compounds on diabetic retinopathy markers, through describing the conducted in vitro and in vivo studies as well as clinical data.

scholarly journals Interactions Between Ephedra sinica and Prunus armeniaca: From Stereoselectivity to Deamination as a Metabolic Detoxification Mechanism of Amygdalin

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Qin ◽  
Shanshan Wang ◽  
Qiuyu Wen ◽  
Quan Xia ◽  
Sheng Wang ◽  
...  
Keyword(s):  
Rat Liver ◽  
Metabolic Pathways ◽  
Liver Microsomes ◽  
Prunus Armeniaca ◽  
Rat Liver Microsomes ◽  
Microbial Enzymes ◽  
Ephedra Sinica ◽  
Metabolic Detoxification ◽  
Detoxification Pathway

Mahuang–Xingren (MX, Ephedra sinica Stapf-Prunus armeniaca L.) is a classic herb pair used in traditional Chinese medicine. This combined preparation reduces the toxicity of Xingren through the stereoselective metabolism of its main active ingredient amygdalin. However, whether stereoselectivity is important in the pharmacokinetic properties of amygdalin either in the traditional decoction or in the dispensing granules is unclear. Amygdalin is hydrolyzed to its metabolite, prunasin, which produces hydrogen cyanide by degradation of the cyano group. A comprehensive study of the metabolic pathway of amygdalin is essential to better understand the detoxification process. In this article, the potential detoxification pathway of MX is further discussed with regard to herb interactions. In this study, the pharmacokinetic parameters and metabolism of amygdalin and prunasin were investigated by comparing the traditional decoction and the dispensing granule preparations. In addition, several potential metabolites were characterized in an incubation system with rat liver microsomes or gut microbial enzymes. The combination of Xingren with Mahuang reduces exposure to D-amygdalin in vivo and contributes to its detoxification, a process that can be further facilitated in the traditional decoction. From the in vitro co-incubation model, 15 metabolites were identified and classified into cyanogenesis and non-cyanogenesis metabolic pathways, and of these, 10 metabolites were described for the first time. The level of detoxified metabolites in the MX traditional decoction was higher than that in the dispensing granules. The metabolism of amygdalin by the gut microbial enzymes occurred more rapidly than that by the rat liver microsomes. These results indicated that combined boiling both herbs during the preparation of the traditional decoction may induce several chemical changes that will influence drug metabolism in vivo. The gut microbiota may play a critical role in amygdalin metabolism. In conclusion, detoxification of MX may result 1) during the preparation of the decoction, in the boiling phase, and 2) from the metabolic pathways activated in vivo. Stereoselective pharmacokinetics and deamination metabolism have been proposed as the detoxification pathway underlying the compatibility of MX. Metabolic detoxification of amygdalin was quite different between the two combinations, which indicates that the MX decoctions should not be completely replaced by their dispensing granules.

Inhibitory Effect of Resveratrol on the Pharmacokinetics of Ticagrelor in Vivo and Vitro

2021 ◽  
Author(s):  
Peng Wang ◽  
Xiao-Xia Hu ◽  
Ying-hui Li ◽  
Nan-Yong Gao ◽  
Guo-quan Chen ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Control Group ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
Group B

This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human CYP3A4 and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50mg/kg resveratrol), and group C (150mg/kg resveratrol ). After 30 minutes administration of resveratrol, a single dose of ticagrelor (18mg/kg) was administered orally. The vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated UHPLC-MS/MS methods. In vivo study, the AUC and Cmax of ticagrelor in group B and C appeared to be significantly higher than the control group, while Vz/F and CLz/F of ticagrelor in group B and C were significantly decreased. In vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The IC50 values of resveratrol were 56.75μM，69.07μM and 14.22μM, respectively. Our results indicated that resveratrol had a inhibitory effect on the metabolism of ticagrelor in vitro and vivo. It should be paid more attention to the clinical combination of resveratrol with ticagrelor and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.

scholarly journals Development of SGC-GAK-1 as an orally active in vivo probe for cyclin G associated kinase through cytochrome P450 inhibition

2019 ◽  
Author(s):  
Christopher R. M. Asquith ◽  
James M. Bennett ◽  
Lianyong Su ◽  
Tuomo Laitinen ◽  
Jonathan M. Elkins ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Liver Microsomes ◽  
Intrinsic Clearance ◽  
In Vivo Studies ◽  
Chemical Probe ◽  
Active Chemical ◽  
Rapid Clearance ◽  
Cyclin G ◽  
Orally Active

AbstractSGC-GAK-1 (1), a potent, selective, cell-active chemical probe for cyclin G associated kinase (GAK), was rapidly metabolized in mouse liver microsomes by P450 mediated oxidation. 1 displayed rapid clearance in mice, limiting its utility for in vivo studies. All chemical modifications of 1 that improved metabolic stability led to a loss in GAK activity. However, pretreatment of liver microsomes with the irreversible cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) decreased intrinsic clearance of 1. Coadministration of ABT also greatly improved plasma exposure of 1 in mice, supporting its use as a chemical probe to study the in vivo biology of GAK inhibition.

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