Effects of polyethylene glycols on intestinal efflux pump expression and activity in Caco-2 cells

The present study was planned to investigate the influence of polyethylene glycols (PEGs) on the activity and expression of P-glycoprotein (P-gp). Sub-toxic concentrations of PEGs in Caco-2 cells were determined using the MTT test assay. Then the measurement of Rhodamine-123 (Rho-123) uptake, a P-gp fluorescence substrate, in Caco-2 cells confronting PEG 400 (1% and 2% w/v), PEG 4000 (2% and 4% w/v), PEG 6000 (2% and 4% w/v), PEG 10000 (2% and 4% w/v), PEG 15000 (1% and 2% w/v), and PEG 35000 (2% and 4% w/v) overnight was taken to elucidate whether non-toxic concentrations of PEGs are able to impact P-gp activity. Furthermore, western blotting was carried out to investigate P-gp protein expression. The results showed that PEG 400 at concentrations of 1% (w/v) and 2% (w/v) and PEG 6000 at the concentration of 4% (w/v) are notably capable of blocking P-gp. Based on the obtained results it is concluded that the mentioned excipients could be used to obstruct P-gp efflux transporter in order to increase the bioavailability of co-administered substrate drug.

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Pharmacokinetic Alteration of Paclitaxel by Ferulic Acid Derivative

Pharmaceutics ◽

10.3390/pharmaceutics11110593 ◽

2019 ◽

Vol 11 (11) ◽

pp. 593 ◽

Cited By ~ 1

Author(s):

Jaeok Lee ◽

Song Wha Chae ◽

LianJi Ma ◽

So Yeon Lim ◽

Sarah Alnajjar ◽

...

Keyword(s):

Multidrug Resistance ◽

Ferulic Acid ◽

Acid Derivative ◽

Glycoprotein P ◽

P Glycoprotein ◽

Substrate Drug

P-glycoprotein (P-gp) is known to be involved in multidrug resistance (MDR) and modulation of pharmacokinetic (PK) profiles of substrate drugs. Here, we studied the effects of synthesized ferulic acid (FA) derivatives on P-gp function in vitro and examined PK alteration of paclitaxel (PTX), a well-known P-gp substrate drug by the derivative. Compound 5c, the FA derivative chosen as a significant P-gp inhibitor among eight FA candidates by in vitro results, increased PTX AUCinf as much as twofold versus the control by reducing PTX elimination in rats. These results suggest that FA derivative can increase PTX bioavailability by inhibiting P-gp existing in eliminating organs.

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Functional Role of P-Glycoprotein and Binding Protein Effect on the Placental Transfer of Lopinavir/Ritonavir in the Ex Vivo Human Perfusion Model

Obstetrics and Gynecology International ◽

10.1155/2009/726593 ◽

2009 ◽

Vol 2009 ◽

pp. 1-6 ◽

Cited By ~ 18

Author(s):

Pierre-Francois Ceccaldi ◽

Laurent Gavard ◽

Laurent Mandelbrot ◽

Elisabeth Rey ◽

Robert Farinotti ◽

...

Keyword(s):

Internal Control ◽

Efflux Pump ◽

Placental Transfer ◽

Ex Vivo ◽

Glycoprotein P ◽

Control Phase ◽

P Glycoprotein ◽

Ciclosporin A ◽

High Albumin

Aims. To study the influence of P-glycoprotein (P-glycoprotein, ABCB1, MDR1) function on placental transfer of lopinavir with ritonavir at different albumin concentrations.Methods. Cotyledons were perfused with lopinavir, ritonavir, and the internal control antipyrin, at various albumin concentrations (10, 30, 40 g/L). After the control phase of each experiment, the P-glycoprotein inhibitor ciclosporin A was added at middle perfusion (45 minutes). Fetal Transfer Rate (FTR) and Clearance Index (CLI) were compared between the 2 phases.Results. In the control phase, the clearance index of lopinavir decreased from 0.401±0.058 to 0.007±0.027, as albumin concentrations increased from 10 g/L to higher concentrations (30, 40 g/L). When adding ciclosporin A at physiological albumin concentrations, the clearance index of lopinavir increased significantly 10.3 fold (95% of CI difference [−0.156,−0.002],P=.046) and became positive for ritonavir.Conclusions. Even at high albumin concentrations, inhibition of placental P-glycoprotein increased placental transfer of lopinavir, suggesting that this efflux pump actively reduces placental transfer of the drug. This mechanism may play a role in fetal exposure to maternal antiretroviral therapy.

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Expression of a human multidrug resistance cDNA (MDR1) in the bone marrow of transgenic mice: resistance to daunomycin-induced leukopenia.

Molecular and Cellular Biology ◽

10.1128/mcb.9.10.4357 ◽

1989 ◽

Vol 9 (10) ◽

pp. 4357-4363 ◽

Cited By ~ 112

Author(s):

H Galski ◽

M Sullivan ◽

M C Willingham ◽

K V Chin ◽

M M Gottesman ◽

...

Keyword(s):

Bone Marrow ◽

Multidrug Resistance ◽

Transgenic Mice ◽

Bone Marrow Cells ◽

Efflux Pump ◽

Multidrug Resistance Gene ◽

Glycoprotein P ◽

P Glycoprotein ◽

Leukocyte Counts ◽

Actin Promoter

The human multidrug resistance gene (MDR1) encodes a drug efflux pump glycoprotein (P-glycoprotein) responsible for resistance to multiple cytotoxic drugs. A plasmid carrying a human MDR1 cDNA under the control of a chicken beta-actin promoter was used to generate transgenic mice in which the transgene was mainly expressed in bone marrow and spleen. Immunofluorescence localization studies showed that P-glycoprotein was present on bone marrow cells. Furthermore, leukocyte counts of the transgenic mice treated with daunomycin did not fall, indicating that their bone marrow was resistant to the cytotoxic effect of the drug. Since bone marrow suppression is a major limitation to chemotherapy, these transgenic mice should serve as a model to determine whether higher doses of drugs can cure previously unresponsive cancers.

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Antimicrobial, Anticancer and Multidrug-Resistant Reversing Activity of Novel Oxygen-, Sulfur- and Selenoflavones and Bioisosteric Analogues

Pharmaceuticals ◽

10.3390/ph13120453 ◽

2020 ◽

Vol 13 (12) ◽

pp. 453

Author(s):

Małgorzata Anna Marć ◽

Annamária Kincses ◽

Bálint Rácz ◽

Muhammad Jawad Nasim ◽

Muhammad Sarfraz ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Treatment ◽

Efflux Pump ◽

Multidrug Resistant ◽

Positive Control ◽

Biological Evaluation ◽

Glycoprotein P ◽

Drug Candidates ◽

P Glycoprotein ◽

Efflux Pump Inhibitors

Multidrug resistance of cancer cells to cytotoxic drugs still remains a major obstacle to the success of chemotherapy in cancer treatment. The development of new drug candidates which may serve as P-glycoprotein (P-gp) efflux pump inhibitors is a promising strategy. Selenium analogues of natural products, such as flavonoids, offer an interesting motif from the perspective of drug design. Herein, we report the biological evaluation of novel hybrid compounds, bearing both the flavone core (compounds 1–3) or a bioisosteric analogue core (compounds 4–6) and the triflyl functional group against Gram-positive and Gram-negative bacteria, yeasts, nematodes, and human colonic adenocarcinoma cells. Results show that these flavones and analogues of flavones inhibited the activity of multidrug resistance (MDR) efflux pump ABCB1 (P-glycoprotein, P-gp). Moreover, the results of the rhodamine 123 accumulation assay demonstrated a dose-dependent inhibition of the abovementioned efflux pump. Three compounds (4, 5, and 6) exhibited potent inhibitory activity, much stronger than the positive control, verapamil. Thus, these chalcogen bioisosteric analogues of flavones become an interesting class of compounds which could be considered as P-gp efflux pump inhibitors in the therapy of MDR cancer. Moreover, all the compounds served as promising adjuvants in the cancer treatment, since they exhibited the P-gp efflux pump modulating activity.

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P-glycoprotein inhibition with verapamil overcomes mometasone resistance in Chronic Sinusitis with Nasal Polyps

Rhinology Journal ◽

10.4193/rhin20.551 ◽

2021 ◽

Vol 0 (0) ◽

pp. 0-0

Author(s):

M.S. Taha ◽

A. Nocera ◽

A. Workman ◽

M.M. Amiji ◽

B.S. Bleier

Keyword(s):

Combination Therapy ◽

Nasal Polyps ◽

Efflux Pump ◽

Test Results ◽

Glycoprotein P ◽

P Glycoprotein ◽

Fold Reduction ◽

Anti Inflammatory ◽

Type 2 Inflammation

Background: P-glycoprotein (P-gp) is a membrane efflux pump which is overexpressed in Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) and promotes Type 2 inflammation. Glucocorticoids (GC) are substrates of P-gp suggesting that overexpression may additionally contribute to GC resistance in CRSwNP. This study aims to determine whether P-gp inhibition using verapamil enhances mometasone retention and efficacy in nasal polyp explants. Methodology: IRB approved study in which organotypic polyp explants were exposed to mometasone (4.15 μg/mL) and verapa- mil (125 μg/mL) as mono and combination therapy. The effect of verapamil on mometasone tissue retention over time was deter- mined using HPLC. The effect of verapamil on mometasone anti-inflammatory function was determined using ELISA for secreted IL-5. Groups were compared using Kruskal-Wallis test. Results: P-gp expression strongly and significantly inversely correlated with mometasone retention 1hr after exposure, with a ne- arly 6-fold reduction in tissue retention between the lowest and highest P-gp expressing polyp explants. P-gp inhibition reversed this effect and significantly improved mometasone retention at 1hr relative to mometasone alone. The combination of mome- tasone and verapamil significantly reduced IL-5 secretion relative to vehicle control and outperformed either treatment alone. Conclusions: Our study confirms that P-gp contributes to mometasone resistance. This P-gp mediated resistance was successfully reversed by addition of the P-gp inhibitor verapamil. Verapamil further significantly enhanced the anti-inflammatory effect of mometasone when given as a combination therapy.

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Pharmacokinetic Interactions of Herbs with Cytochrome P450 and P-Glycoprotein

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/736431 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 41

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.

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Temperature dependent physicochemical studies of polyethylene glycols (PEG-400 and PEG-4000) in aqueous sorbitol solutions

Journal of Molecular Liquids ◽

10.1016/j.molliq.2018.07.101 ◽

2018 ◽

Vol 268 ◽

pp. 700-706 ◽

Cited By ~ 11

Author(s):

Kirandeep Kaur ◽

K.C. Juglan ◽

Harsh Kumar

Keyword(s):

Polyethylene Glycols ◽

Temperature Dependent ◽

Peg 400 ◽

Peg 4000 ◽

Physicochemical Studies

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A Physiologically-Based Pharmacokinetic Model of Trimethoprim for MATE1, OCT1, OCT2, and CYP2C8 Drug–Drug–Gene Interaction Predictions

Pharmaceutics ◽

10.3390/pharmaceutics12111074 ◽

2020 ◽

Vol 12 (11) ◽

pp. 1074

Author(s):

Denise Türk ◽

Nina Hanke ◽

Thorsten Lehr

Keyword(s):

Open Systems ◽

Hepatic Clearance ◽

Gene Interaction ◽

Tubular Secretion ◽

Glycoprotein P ◽

Time Profiles ◽

Physiologically Based Pharmacokinetic ◽

P Glycoprotein ◽

Physiologically Based ◽

Intestinal Efflux

Trimethoprim is a frequently-prescribed antibiotic and therefore likely to be co-administered with other medications, but it is also a potent inhibitor of multidrug and toxin extrusion protein (MATE) and a weak inhibitor of cytochrome P450 (CYP) 2C8. The aim of this work was to develop a physiologically-based pharmacokinetic (PBPK) model of trimethoprim to investigate and predict its drug–drug interactions (DDIs). The model was developed in PK-Sim®, using a large number of clinical studies (66 plasma concentration–time profiles with 36 corresponding fractions excreted in urine) to describe the trimethoprim pharmacokinetics over the entire published dosing range (40 to 960 mg). The key features of the model include intestinal efflux via P-glycoprotein (P-gp), metabolism by CYP3A4, an unspecific hepatic clearance process, and a renal clearance consisting of glomerular filtration and tubular secretion. The DDI performance of this new model was demonstrated by prediction of DDIs and drug–drug–gene interactions (DDGIs) of trimethoprim with metformin, repaglinide, pioglitazone, and rifampicin, with all predicted DDI and DDGI AUClast and Cmax ratios within 1.5-fold of the clinically-observed values. The model will be freely available in the Open Systems Pharmacology model repository, to support DDI studies during drug development.

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