scholarly journals In vitro and in situ effects of atorvastatin and ezetimibe on P-glycoprotein expression and function

2016 ◽  
Vol 11 (4) ◽  
pp. 911
Author(s):  
Mehran Mesgari Abbasi ◽  
Hadi Valizadeh ◽  
Hamed Hamishehkar ◽  
Maryam Bannazadeh Amirkhiz ◽  
Parvin Zakeri-Milani
Keyword(s):  
Intestinal Permeability ◽  
High Performance ◽  
Video Clip ◽  
Permeability Model ◽  
Active Efflux ◽  
Single Pass ◽  
P Glycoprotein ◽  
And Function

<p class="Abstract">P-glycoprotein (P-gp) is a membrane transporter responsible for the active efflux from the cell. Inhibition of the activity may lead to clinically significant drug-drug interactions. This study was performed to investigate the effects of atorvastatin and ezetimibe on the function and expression of P-gp. The <em>in vitro</em> rhodamine-123 (Rho123) efflux assay and Western blot in Caco-2 cells, and the <em>in situ</em> rat single-pass intestinal permeability model followed by high performance liquid chromatography were developed. Rho123 intracellular accumulation in 100 µM of atorvastatin- and ezetimibe-treated cells was significantly higher than that in control cells (p&lt;0.05). P-gp expression was decreased by 100 µM atorvastatin and ezetimibe. Intestinal effective permeability of digoxin in the presence of atorvastatin (3 and 100 µM), ezetimibe (10 and 100 µM) was significantly increased (p&lt;0.05). Both drugs  inhibited P-gp activity in vitro and<em> in situ</em>. Atorvastatin and ezetimibe down-regulated the expression of P-gp <em>in vitro</em>. </p><p class="Abstract"><strong>Video Clip of Methodology</strong>:</p><p class="Abstract"><a href="https://youtube.com/v/BQuz1ER3_NQ">Single-pass intestinal permeability</a>: 17 min 26 sec</p><p> </p>

scholarly journals Inhibitory Effect of Berberine on Broiler P-glycoprotein Expression and Function: In Situ and In Vitro Studies

2019 ◽  
Vol 20 (8) ◽  
pp. 1966 ◽  
Author(s):  
Yujuan Zhang ◽  
Li Guo ◽  
Jinhu Huang ◽  
Yong Sun ◽  
Fang He ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Inhibitory Effect ◽  
In Vitro Models ◽  
Apparent Permeability ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
And Function ◽  
Xenobiotic Receptor

Overcoming P-glycoprotein (P-gp) efflux is a strategy to improve the absorption and pharmacokinetics of its substrate drugs. Berberine inhibits P-gp and thereby increases the bioavailability of the P-gp substrate digoxin in rodents. However, the effects of berberine on P-gp in chickens are still unclear. Here, we studied the role of berberine in modulating broilers P-gp expression and function through both in situ and in vitro models. In addition, molecular docking was applied to analyze the interactions of berberine with P-gp as well as with chicken xenobiotic receptor (CXR). The results showed that the mRNA expression levels of chicken P-gp and CXR decreased in the ileum following exposure to berberine. The absorption rate constant of rhodamine 123 increased after berberine treatment, as detected using an in situ single-pass intestinal perfusion model. Efflux ratios of P-gp substrates (tilmicosin, ciprofloxacin, clindamycin, ampicillin, and enrofloxacin) decreased and the apparent permeability coefficients increased after co-incubation with berberine in MDCK-chAbcb1 cell models. Bidirectional assay results showed that berberine could be transported by chicken P-gp with a transport ratio of 4.20, and this was attenuated by verapamil (an inhibitor of P-gp), which resulted in a ratio of 1.13. Molecular docking revealed that berberine could form favorable interactions with the binding pockets of both CXR and P-gp, with docking scores of −7.8 and −9.5 kcal/mol, respectively. These results indicate that berberine is a substrate of chicken P-gp and down-regulates P-gp expression in chicken tissues, thereby increasing the absorption of P-gp substrates. Our findings suggest that berberine increases the bioavailability of other drugs and that drug-drug interactions should be considered when it is co-administered with other P-gp substrates with narrow therapeutic windows.

scholarly journals The Effects of Cetirizine on P-glycoprotein Expression and Function In vitro and In situ

2016 ◽  
Vol 6 (1) ◽  
pp. 111-118 ◽  
Author(s):  
Mehran Mesgari Abbasi ◽  
Hadi Valizadeh ◽  
Hamed Hamishekar ◽  
Leila Mohammadnejad ◽  
Parvin Zakeri-Milani
Keyword(s):  
P Glycoprotein ◽  
And Function

scholarly journals Soybean Oil-Based Lipid Emulsion Increases Intestinal Permeability of Lipopolysaccharide in Caco-2 Cells by Downregulation of P-Glycoprotein via ERK-FOXO 3a Pathway

2016 ◽  
Vol 39 (4) ◽  
pp. 1581-1594 ◽  
Author(s):  
Jun-Kai Yan ◽  
Jie Zhu ◽  
Bei-Lin Gu ◽  
Wei-Hui Yan ◽  
Yong-Tao Xiao ◽  
...  
Keyword(s):  
Soybean Oil ◽  
Intestinal Permeability ◽  
Lipid Emulsion ◽  
Major Complication ◽  
Underlying Mechanism ◽  
Inhibitory Effect ◽  
Cell Monolayers ◽  
P Glycoprotein ◽  
And Function

Background and Aims: Elevated intestinal permeability of lipopolysaccharide (LPS) is a major complication for patients with parenteral nutrition (PN), but the pathogenesis is poorly understood. Intestinal P-glycoprotein (P-gp) is one of the efflux transporters that contribute to restricting the permeability of lipopolysaccharide via transcellular route. P-gp expression may be regulated by PN ingredients, and thus this study sought to investigate the effect of PN on the expression of P-gp and to elucidate the underlying mechanism in vitro. Methods: Caco-2 cells were treated with PN ingredients. Changes in P-gp expression and function were determined and the role of ERK-FOXO 3a pathway was studied. Transport studies of FITC-lipopolysaccharide (FITC-LPS) across Caco-2 cell monolayers were also performed. Results: Among PN ingredients, soybean oil-based lipid emulsion (SOLE) exhibited significant inhibitory effect on P-gp expression and function. This regulation was mediated via activation of ERK pathway with subsequent nuclear exclusion of FOXO 3a. Importantly, P-gp participated in antagonizing the permeation of FITC-LPS (apical to basolateral) across Caco-2 cell monolayers. SOLE significantly increased the permeability of FITC-LPS (apical to basolateral), which was associated with impaired P-gp function. Conclusions: The expression and function of intestinal P-gp is suppressed by SOLE in vitro.

scholarly journals Overexpression of P-glycoprotein, MRP2, and CYP3A4 impairs intestinal absorption of octreotide in rats with portal hypertension

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiaoyu Sun ◽  
Shunxiong Tang ◽  
Binbin Hou ◽  
Zhijun Duan ◽  
Zhen Liu ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Portal Hypertension ◽  
Western Blot ◽  
In Vitro Experiments ◽  
Rt Pcr ◽  
P Glycoprotein ◽  
Intestinal Microsomes ◽  
First Pass

Abstract Background Portal hypertension (PH) is the main cause of complications and death in liver cirrhosis. The effect of oral administration of octreotide (OCT), a drug that reduces PH by the constriction of mesenteric arteries, is limited by a remarkable intestinal first-pass elimination. Methods The bile duct ligation (BDL) was used in rats to induce liver cirrhosis with PH to examine the kinetics and molecular factors such as P-glycoprotein (P-gp), multidrug resistance-associated protein 2 (MRP2) and cytochrome P450 3A4 (CYP3A4) influencing the intestinal OCT absorption via in situ and in vitro experiments on jejunal segments, transportation experiments on Caco-2 cells and experiments using intestinal microsomes and recombinant human CYP3A4. Moreover, RT-PCR, western blot, and immunohistochemistry were performed. Results Both in situ and in vitro experiments in jejunal segments showed that intestinal OCT absorption in both control and PH rats was largely controlled by P-gp and, to a lesser extent, by MRP2. OCT transport mediated by P-gp and MRP2 was demonstrated on Caco-2 cells. The results of RT-PCR, western blot, and immunohistochemistry suggested that impaired OCT absorption in PH was in part due to the jejunal upregulation of these two transporters. The use of intestinal microsomes and recombinant human CYP3A4 revealed that CYP3A4 metabolized OCT, and its upregulation in PH likely contributed to impaired drug absorption. Conclusions Inhibition of P-gp, MRP2, and CYP3A4 might represent a valid option for decreasing intestinal first-pass effects on orally administered OCT, thereby increasing its bioavailability to alleviate PH in patients with cirrhosis.

Intestinal transport of HDND-7, a novel hesperetin derivative, in in vitro MDCK cell and in situ single-pass intestinal perfusion models

Xenobiotica ◽  
2016 ◽  
Vol 47 (8) ◽  
pp. 719-730 ◽  
Author(s):  
Ruonan Chen ◽  
Lan Li ◽  
Chenlin Shen ◽  
Cheng Huang ◽  
Taotao Ma ◽  
...  
Keyword(s):  
Mdck Cell ◽  
Intestinal Transport ◽  
Intestinal Perfusion ◽  
Single Pass

Investigation of the Intestinal Permeability of Ciclosporin Using the in situ Technique in Rats and the Relevance of P-Glycoprotein

2011 ◽  
Vol 58 (04) ◽  
pp. 188-192
Author(s):  
Parvin Zakeri-Milani ◽  
Hadi Valizadeh ◽  
Ziba Islambulchilar ◽  
Sanaz Damani ◽  
Maryam Mehtari
Keyword(s):  
Intestinal Permeability ◽  
P Glycoprotein ◽  
In Situ Technique

scholarly journals Altered folate binding protein expression and folate delivery are associated with congenital hydrocephalus in the hydrocephalic Texas rat

2018 ◽  
Vol 39 (10) ◽  
pp. 2061-2073 ◽  
Author(s):  
Alicia Requena Jimenez ◽  
Naila Naz ◽  
Jaleel A Miyan
Keyword(s):  
Folate Receptor ◽  
Cortical Cell ◽  
Regulatory Function ◽  
Folate Binding Protein ◽  
In Vitro Proliferation ◽  
Cycle Arrest ◽  
Csf Levels ◽  
And Function

Hydrocephalus (HC) is an imbalance in cerebrospinal fluid (CSF) secretion/absorption resulting in fluid accumulation within the brain with consequential pathophysiology. Our research has identified a unique cerebral folate system in which depletion of CSF 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is associated with cortical progenitor cell-cycle arrest in hydrocephalic Texas (H-Tx) rats. We used tissue culture, immunohistochemistry, in-situ PCR and RT-PCR and found that the in-vitro proliferation of arachnoid cells is highly folate-dependent with exacerbated proliferation occurring in hydrocephalic CSF that has low FDH but high folate-receptor-alpha (FRα) and folate. Adding FDH to this CSF prevented aberrant proliferation indicating a regulatory function of FDH on CSF folate concentration. Arachnoid cells have no detectable mRNA for FRα or FDH, but FDH mRNA is found in the choroid plexus (CP) and CSF microvesicles. Co-localization of FDH, FRα and folate suggests important functions of FDH in cerebral folate transport, buffering and function. In conclusion, abnormal CSF levels of FDH, FRα and folate inhibit cortical cell proliferation but allow uncontrolled arachnoid cell division that should increase fluid absorption by increasing the arachnoid although this fails in the hydrocephalic brain. FDH appears to buffer available folate to control arachnoid proliferation and function.

scholarly journals INFLUENCE OF POLYSACCHARIDE COMPLEXES OF PLANTS OF CENTRAL RUSSIA ON THE P-GLYCOPROTEIN ACTIVITY IN VITRO

2020 ◽  
pp. 73-81
Author(s):  
Ivan Vladimirovich Chernykh ◽  
Aleksey Vladimirovich Shchul'kin ◽  
Yekaterina Yevgen'yevna Kirichenko ◽  
Sergey Konstantinovich Pravkin ◽  
Yelena Nikolayevna Yakusheva
Keyword(s):  
High Performance ◽  
Protein Activity ◽  
Apparent Permeability ◽  
Melilotus Officinalis ◽  
Polysaccharide Complex ◽  
Transport Medium ◽  
Transporter Protein ◽  
Central Russia ◽  
P Glycoprotein

The purpose of this work was to study the effect of polysaccharide complexes isolated from tansy flowers (Tanacetum vulgare L., fam. Asteraceae) and melilotus herb (Melilotus officinalis L., fam. Fabaceae) on P-glycoprotein (Pgp, ABCB1 protein) activity in vitro. On Caco-2 cell line the effect of polysaccharide complex isolated from tansy flowers and melilotus herb on Pgp activity was studied. In vitro Pgp activity was assessed by the transport of fexofenadine in the transwell system. High performance liquid chromatography with UV detection at wavelength 220 nm was used to determine fexofenadine concentration in the transport medium. It was revealed that when polysaccharide isolated from tansy flowers was added to the transport medium in concentrations 10 and 100 μM the ratio of the apparent permeability coefficients of fexofenadine b-a/a-b decreased by 1.81 and 2.65 times, respectively, compared with the series of isolated transport of fexofenadine, which indicated decreased Pgp functional activity under the polysaccharide action. The polysaccharide complex of the melilotus herb did not change the b-a/a-b ratio in any of the applied concentrations, thus it did not affect the activity of this transporter. It is advisable to continue the study of tansy flower polysaccharide complex as an inhibitor of Pgp transporter protein in order to assess the possibility of its clinical use for the treatment of pharmacoresistant forms of cancer by overcoming the phenomenon of multidrug resistance of cells.

Assessment of Ferrous Glycinate Liposome Absorption Using in Situ Single-Pass Perfusion Model

2017 ◽  
Vol 13 (9) ◽  
Author(s):  
Baomiao Ding ◽  
Xiangzhou Yi ◽  
Li Li ◽  
Hualin Yang
Keyword(s):  
Particle Size ◽  
Phytic Acid ◽  
Intestinal Permeability ◽  
Iron Absorption ◽  
Inhibitory Effects ◽  
Single Pass ◽  
Pass Perfusion ◽  
Absorption Pathways ◽  
Main Factor

AbstractLiposomes could be employed to improve the absorption of iron. The purpose of this study was to estimate the intestinal permeability of ferrous glycinate liposomes and to assess the effects of phytic acid, zinc and particle size on iron absorption usingin situsingle-pass perfusion in rats. The results showed that the absorption of ferrous glycinate liposomes was obviously higher than that of ferrous glycinate. The inhibitory effects of phytic acid and zinc on iron absorption were reduced by incorporating ferrous glycinate into liposomes. The particle size of ferrous glycinate liposomes was also a main factor for affecting iron absorption, and the intestinal permeability of the liposomes decreased with its particle size increasing. The results suggested that liposomes could be a potent delivery system to decrease the inhibitory effects of phytic acid and zinc and to enhance iron absorption. Furthermore, liposomes could alter the absorption pathways of ferrous glycinate.

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