Comparing Various In Vitro Prediction Methods to Assess the Potential of a Drug to Inhibit P‐glycoprotein (P‐gp) Transporter In Vivo

2019 ◽  
Vol 59 (8) ◽  
pp. 1049-1060 ◽  
Author(s):  
Tian Zhou ◽  
Vikram Arya ◽  
Lei Zhang
Keyword(s):  
Prediction Methods ◽  
Glycoprotein P ◽  
P Glycoprotein

scholarly journals Upregulations of Clcn3 and P-Gp Provoked by Lens Osmotic Expansion in Rat Galactosemic Cataract

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Lixia Ji ◽  
Lixia Cheng ◽  
Zhihong Yang
Keyword(s):  
Osmotic Stress ◽  
Early Stage ◽  
Lens Epithelial Cells ◽  
Anterior Capsule ◽  
Glycoprotein P ◽  
Protein Levels ◽  
P Glycoprotein ◽  
Sugar Cataract

Objective.Lens osmotic expansion, provoked by overactivated aldose reductase (AR), is the most essential event of sugar cataract. Chloride channel 3 (Clcn3) is a volume-sensitive channel, mainly participating in the regulation of cell fundamental volume, and P-glycoprotein (P-gp) acts as its modulator. We aim to study whether P-gp and Clcn3 are involved in lens osmotic expansion of galactosemic cataract.Methods and Results.In vitro, lens epithelial cells (LECs) were primarily cultured in gradient galactose medium (10–60 mM), more and more vacuoles appeared in LEC cytoplasm, and mRNA and protein levels of AR, P-gp, and Clcn3 were synchronously upregulated along with the increase of galactose concentration. In vivo, we focused on the early stage of rat galactosemic cataract, amount of vacuoles arose from equatorial area and scattered to the whole anterior capsule of lenses from the 3rd day to the 9th day, and mRNA and protein levels of P-gp and Clcn3 reached the peak around the 9th or 12th day.Conclusion. Galactosemia caused the osmotic stress in lenses; it also markedly leads to the upregulations of AR, P-gp, and Clcn3 in LECs, together resulting in obvious osmotic expansion in vitro and in vivo.

scholarly journals Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo

2019 ◽  
Vol 442 ◽  
pp. 91-103 ◽  
Author(s):  
Albert A. De Vera ◽  
Pranav Gupta ◽  
Zining Lei ◽  
Dan Liao ◽  
Silpa Narayanan ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein

Dietary Nucleotide Supplements in Infant Formula Modify the Expression of P-glycoprotein in the Intestinal Epithelium in vitro

2009 ◽  
Vol 79 (56) ◽  
pp. 381-387 ◽  
Author(s):  
Mary Bebawy ◽  
Christine Rasmussen ◽  
Shwetha Sambasivam ◽  
Shisan Bao
Keyword(s):  
Infant Formula ◽  
Dependent Manner ◽  
Drug Bioavailability ◽  
Concentration Dependent Manner ◽  
Glycoprotein P ◽  
Colon Cells ◽  
P Glycoprotein ◽  
Dietary Nucleotides

The effect of dietary nucleotides at concentrations found in supplemented infant formula on P-glycoprotein (P-gp) expression in colon cells was examined. We report that P-gp expression in colon cells was significantly decreased in a time- and concentration-dependent manner. When colon cells were co-cultured with lymphocytes, so as to mimic the involvement of gut-associated lymphoid tissue in normal gut pathophysiology, we observed a reversal of this effect with a demonstrated increase in P-gp expression. These findings have important implications on effects of nucleotide exposure on increasing drug bioavailability, reducing the capacity for xenobiotic efflux, and increasing the risk of inflammatory bowel disease in susceptible infants. Future studies are directed at defining both the mechanisms underlying these findings and effects of dietary nucleotide supplementation in vivo.

scholarly journals Pharmacokinetic Interactions of Herbs with Cytochrome P450 and P-Glycoprotein

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Hyun-Jong Cho ◽  
In-Soo Yoon
Keyword(s):  
Cytochrome P450 ◽  
Glycoprotein P ◽  
Metabolizing Enzymes ◽  
Herbal Products ◽  
P Glycoprotein ◽  
Concurrent Use ◽  
Substrate Drug ◽  
And Function

The concurrent use of drugs and herbal products is becoming increasingly prevalent over the last decade. Several herbal products have been known to modulate cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp) which are recognized as representative drug metabolizing enzymes and drug transporter, respectively. Thus, a summary of knowledge on the modulation of CYP and P-gp by commonly used herbs can provide robust fundamentals for optimizing CYP and/or P-gp substrate drug-based therapy. Herein, we review ten popular medicinal and/or dietary herbs as perpetrators of CYP- and P-gp-mediated pharmacokinetic herb-drug interactions. The main focus is placed on previous works on the ability of herbal extracts and their phytochemicals to modulate the expression and function of CYP and P-gp in severalin vitroandin vivoanimal and human systems.

scholarly journals Intestinal P-glycoprotein Expression is Multimodally Regulated by Intestinal Ischemia-Reperfusion

2014 ◽  
Vol 17 (2) ◽  
pp. 266 ◽  
Author(s):  
Yusuke Terada ◽  
Jiro Ogura ◽  
Takashi Tsujimoto ◽  
Kaori Kuwayama ◽  
Takahiro Koizumi ◽  
...  
Keyword(s):  
Intestinal Ischemia ◽  
Ischemia Reperfusion ◽  
Tacrolimus Concentration ◽  
Glycoprotein P ◽  
In Vivo Experiments ◽  
P Glycoprotein ◽  
Blood Tacrolimus Concentration ◽  
Intestinal Ischemia Reperfusion

Purpose. Reactive oxygen species (ROS) have multiple physiological effects that are amount-dependent. ROS are one of the causes of intestinal ischemia-reperfusion (I/R) injury. In this study, we investigated whether the amount of ROS and the degree of intestinal I/R injury affect the expression level of P-glycoprotein (P-gp). Methods. We used hydrogen peroxide (H2O2) as ROS in in vitro experiments. Intestinal I/R model rats, which were subjected 15-min ischemia (I/R-15), were used in in vivo experiments. Results. P-gp expression in Caco-2 cells was increased in response to 1 µM of H2O2 but decreased upon exposure to 10 mM of H2O2. We previously reported that P-gp expression is decreased after intestinal I/R with 30-min ischemia (I/R-30), which time a large amount of ROS is generated. I/R-15 induced slightly less mucosal and oxidative injury than did I/R-30. P-gp expression in the jejunum was increased at 1 h after I/R-15, and ileal paracellular permeability was increased. The blood concentration of tacrolimus, a P-gp substrate, was lower during 0-20 min but was higher during 40-90 min post-administration compared with that in the sham-operated rats. P-gp expression in the ileum was decreased at 6 h after I/R-15, due to abnormal localization of P-gp, resulting in a high blood tacrolimus concentration in rats reperfused for 6 h. Conclusions. ROS multimodally regulate P-gp expression depending on its amount. This is important for understanding the pattern of P-gp expression after intestinal I/R. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

scholarly journals Bevacizumab and Sorafenib Modulate P-Glycoprotein Function In Vitro and Bevacizumab Increases In Vivo Sorafenib Plasma Concentrations in Mice

2020 ◽  
Vol 5 (08) ◽  
pp. 261-267
Author(s):  
Mahamadou Tandia ◽  
Chadi Abbara ◽  
Marie-Sophie Noel-Hudson ◽  
Dora Amor ◽  
Mélanie Polrot ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Vascular Endothelial ◽  
Intracellular Accumulation ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Pretreated Group ◽  
Human Ovarian Carcinoma ◽  
Endothelial Growth Factor

Overexpression of P-glycoprotein (P-gp) is associated with multidrug resistance. Since sorafenib (NEXAVAR®) is a P-gp (an efflux protein of ATP-binding cassette family) substrate, we tested whether bevacizumab (AVASTIN®), a monoclonal antibody directed toward VEGF (Vascular Endothelial Growth Factor) and sorafenib could modulate P-gp functionality. In vitro two human ovarian carcinoma cells (IGROV1) overexpressing or weakly expressing P-gp were used. Bevacizumab and sorafenib effects on P-gp functionality were evaluated by measuring doxorubicin intracellular accumulation. In vivo study was to document whether bevacizumab could modify sorafenib disposition in mice. Therefore, concentrations of sorafenib were determined by HPLC in plasma of mice bearing a human colorectal carcinoma xenograft when sorafenib is given orally (5 mg/kg) on day 4, alone or after a pretreatment with bevacizumab (5 mg/kg IP) on days 1 and 3. In vitro a significant doxorubicin accumulation and reversion of doxorubicin resistance in  P-gp expressing cell lines were observed with bevacizumab or sorafenib pretreatment In vivo, sorafenib AUC was 1.44 fold significantly higher in bevacizumab pretreated group and Cmax was 1.35 fold higher in bevacizumab-pretreated group. Mean residence time of sorafenib increased in the presence of bevacizumab, this increase reflects an improvement of sorafenib bioavailability after bevacizumab pretreatment. We may conclude that bevacizumab pretreatment decreases P-gp functionality and increases doxorubicin intracellular accumulation in vitro and sorafenib plasma concentrations in vivo.

scholarly journals P-glycoprotein Mediated Efflux Modulators of Plant Origin: A Short Review

2016 ◽  
Vol 11 (5) ◽  
pp. 1934578X1601100 ◽  
Author(s):  
Nuno Silva ◽  
Lígia Salgueiro ◽  
Ana Fortuna ◽  
Carlos Cavaleiro
Keyword(s):  
Short Review ◽  
Efflux Transporters ◽  
Drug Efflux ◽  
Plant Origin ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Plant Compounds ◽  
Drug Efflux Transporters

Drug efflux transporters such as P-glycoprotein (P-gp) help maintain cellular homeostasis but are also major contributors to the development of multidrug resistance (MDR) phenomena. Since P-gp was associated with MDR, several compounds showing potential to inhibit this transporter have been identified. Particular attention has been given to natural products, namely those of plant origin, looking for highly effective and safe P-gp inhibitors with little to no interaction with other cellular or metabolic processes. Here we abridge several examples of plant compounds from distinct classes, polyketides, lignans, anthraquinones, coumarins, alkaloids, mono- and sesqui-terpenes, steroids and limonoids, which have shown the ability to modulate in vitro or in vivo the P-gp activity.

scholarly journals Acetaminophen (AP) inhibits intestinal P‐glycoprotein (P‐gp) activity in vitro and in vivo.

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Analía Novak ◽  
Griselda Delli Carpini ◽  
María Laura Ruiz ◽  
Marcelo Luquita ◽  
Modesto Carlos Rubio ◽  
...  
Keyword(s):  
Glycoprotein P ◽  
P Glycoprotein
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