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

2009 ◽  
Vol 2009 ◽  
pp. 1-6 ◽  
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.

Influence of adenosine triphosphate and ABCB1 (MDR1) genotype on the P-glycoprotein-dependent transfer of saquinavir in the dually perfused human placenta

2008 ◽  
Vol 27 (1) ◽  
pp. 65-71 ◽  
Author(s):  
M Rahi ◽  
T Heikkinen ◽  
J Hakkola ◽  
K Hakala ◽  
O Wallerman ◽  
...  
Keyword(s):  
Human Placenta ◽  
Efflux Pump ◽  
Placental Transfer ◽  
Wild Type ◽  
Perfusion Medium ◽  
Tissue Penetration ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Drug Efflux Pump ◽  
Dose Response Effect

Background: The ATP-dependent drug-efflux pump, P-glycoprotein (P-gp) encoded by ABCB1 (MDR1), plays a crucial role in several tissues forming blood–tissue barriers. Absence of a normally functioning P-gp can lead to a highly increased tissue penetration of a number of clinically important drugs. Methods: We have studied the dose–response effect of exogenous ATP on the placental transfer of the well-established P-gp substrate saquinavir in 17 dually perfused human term placentas. We have also studied the influence of the ABCB1 polymorphisms 2677G>T/A and 3435C>T on placental P-gp expression ( n = 44) and the transfer ( n = 16) of saquinavir. Results: The present results indicate that the addition of exogenous ATP to the perfusion medium does not affect the function of P-gp as measured by saquinavir transfer across the human placenta. The variant allele 3435T was associated with significantly higher placental P-gp expression than the wild-type alleles. However, neither polymorphism affected placental transfer of saquinavir nor there was any correlation between P-gp expression and saquinavir transfer. Conclusions: Our results indicate that addition of exogenous ATP is not required for ATP-dependent transporter function in a dually perfused human placenta. Although the ABCB1 polymorphism 3435C>T altered the expression levels of P-gp in the human placenta, this did not have any consequences on P-gp–mediated placental transfer of saquinavir.

scholarly journals Human P-glycoprotein differentially affects antidepressant drug transport: relevance to blood–brain barrier permeability

2013 ◽  
Vol 16 (10) ◽  
pp. 2259-2272 ◽  
Author(s):  
Fionn E. O'Brien ◽  
Gerard Clarke ◽  
Timothy G. Dinan ◽  
John F. Cryan ◽  
Brendan T. Griffin
Keyword(s):  
Drug Transport ◽  
Efflux Pump ◽  
Antidepressant Drug ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Brain Barrier Permeability ◽  
Antidepressant Imipramine ◽  
Bidirectional Transport ◽  
Insight Into

Abstract The pharmacological concept that inhibition of the drug efflux pump P-glycoprotein (P-gp) enhances brain distribution of the antidepressant imipramine in the rat has recently been demonstrated. To determine if these findings are relevant to humans, the present study investigated if imipramine is a transported substrate of human P-gp. Furthermore, additional experiments were carried out to determine if findings in relation to imipramine and human P-gp would apply to other antidepressants from a range of different classes. To this end, bidirectional transport experiments were carried out in the ABCB1-transfected MDCKII-MDR1 cell line. Transported substrates of human P-gp are subjected to net efflux in this system, exhibiting a transport ratio (TR) ⩾ 1.5, and directional efflux is attenuated by co-incubation of a P-gp inhibitor. Imipramine was identified as a transported substrate of human P-gp (TR = 1.68, attenuated by P-gp inhibition). However, the antidepressants amitriptyline, duloxetine, fluoxetine and mirtazapine were not transported substrates of human P-gp (TR ⩽ 1.16 in all cases). These results offer insight into the role of P-gp in the distribution of antidepressants, revealing that rodent findings pertaining to imipramine may translate to humans. Moreover, the present results highlight that other antidepressants may not be transported substrates of human P-gp.

scholarly journals Characterization and tissue localization of zebrafish homologs of the human ABCB1 multidrug transporter

2021 ◽  
Author(s):  
Robert W. Robey ◽  
Andrea N. Robinson ◽  
Fatima Ali-Rahmani ◽  
Lyn M. Huff ◽  
Sabrina Lusvarghi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Multidrug Transporter ◽  
Glycoprotein P ◽  
Tissue Localization ◽  
Brain Vasculature ◽  
P Glycoprotein ◽  
Capillary Endothelial Cells ◽  
The Brain ◽  
Viable Model

ABSTRACTGiven its similarities with mammalian systems, the zebrafish has emerged as a potential model to study the blood-brain barrier (BBB). Capillary endothelial cells at the human BBB express high levels of P-glycoprotein (P-gp, encoded by the ABCB1 gene) and ABCG2 (encoded by the ABCG2 gene). However, little information has been available about ATP-binding cassette transporters expressed at the zebrafish BBB. In this study, we focus on the characterization and tissue localization of two genes that are similar to human ABCB1, zebrafish abcb4 and abcb5. Cytotoxicity assays with stably-transfected cell lines revealed that zebrafish Abcb5 cannot efficiently transport the substrates doxorubicin and mitoxantrone compared to human P-gp and zebrafish Abcb4. Additionally, zebrafish Abcb5 did not transport the fluorescent probes BODIPY-ethylenediamine or LDS 751, while they were readily transported by Abcb4 and P-gp. A high-throughput screen conducted with 90 human P-gp substrates confirmed that zebrafish Abcb4 has overlapping substrate specificity with P-gp. Basal ATPase activity of zebrafish Abcb4 and Abcb5 was comparable to that of human P-gp. In the brain vasculature, RNAscope probes to detect abcb4 colocalized with staining by the P-gp antibody C219, while abcb5 was not detected. Zebrafish abcb4 also colocalized with claudin-5 expression in brain endothelial cells. Abcb4 and Abcb5 had different tissue localizations in multiple zebrafish tissues, consistent with different functions. The data suggest that zebrafish Abcb4 most closely phenocopies P-gp and that the zebrafish may be a viable model to study the role of the multidrug transporter P-gp at the BBB.

scholarly journals Verification of P-Glycoprotein Function at the Dermal Barrier in Diffusion Cells and Dynamic “Skin-On-A-Chip” Microfluidic Device

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 804
Author(s):  
Ágnes Bajza ◽  
Dorottya Kocsis ◽  
Orsolya Berezvai ◽  
András József Laki ◽  
Bence Lukács ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Ex Vivo ◽  
Topical Administration ◽  
Transdermal Absorption ◽  
P Glycoprotein ◽  
Diffusion Cells ◽  
Defensive Role ◽  
Dermal Drug Delivery

The efficacy of transdermal absorption of drugs and the irritation or corrosion potential of topically applied formulations are important areas of investigation in pharmaceutical, military and cosmetic research. The aim of the present experiments is to test the role of P-glycoprotein in dermal drug delivery in various ex vivo and in vitro platforms, including a novel microchip technology developed by Pázmány Péter Catholic University. A further question is whether the freezing of excised skin and age have any influence on P-glycoprotein-mediated dermal drug absorption. Two P-glycoprotein substrate model drugs (quinidine and erythromycin) were investigated via topical administration in diffusion cells, a skin-on-a-chip device and transdermal microdialysis in rat skin. The transdermal absorption of both model drugs was reduced by P-glycoprotein inhibition, and both aging and freezing increased the permeability of the tissues. Based on our findings, it is concluded that the process of freezing leads to reduced function of efflux transporters, and increases the porosity of skin. P-glycoprotein has an absorptive orientation in the skin, and topical inhibitors can modify its action. The defensive role of the skin seems to be diminished in aged individuals, partly due to reduced thickness of the dermis. The novel microfluidic microchip seems to be an appropriate tool to investigate dermal drug delivery.

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

1989 ◽  
Vol 9 (10) ◽  
pp. 4357-4363 ◽  
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.

scholarly journals Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3364 ◽  
Author(s):  
Bruno M. F. Gonçalves ◽  
David S. P. Cardoso ◽  
Maria-José U. Ferreira
Keyword(s):  
Multidrug Resistance ◽  
Natural Product ◽  
Abc Transporter ◽  
Efflux Pumps ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
Multidrug Resistance Protein 1 ◽  
P Glycoprotein ◽  
Resistance Protein

Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

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

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.

scholarly journals Newly Synthesized Oxygenated Xanthones as Potential P-Glycoprotein Activators: In Vitro, Ex Vivo, and In Silico Studies

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 707 ◽  
Author(s):  
Eva Martins ◽  
Vera Silva ◽  
Agostinho Lemos ◽  
Andreia Palmeira ◽  
Ploenthip Puthongking ◽  
...  
Keyword(s):  
In Silico ◽  
Crucial Role ◽  
Ex Vivo ◽  
Glycoprotein P ◽  
Docking Simulations ◽  
Knowing That ◽  
P Glycoprotein ◽  
In Silico Studies ◽  
Gp Model

P-glycoprotein (P-gp) plays a crucial role in the protection of susceptible organs, by significantly decreasing the absorption/distribution of harmful xenobiotics and, consequently, their toxicity. Therefore, P-gp has been proposed as a potential antidotal pathway, when activated and/or induced. Knowing that xanthones are known to interact with P-gp, the main goal was to study P-gp induction or/and activation by six new oxygenated xanthones (OX 1-6). Furthermore, the potential protection of Caco-2 cells against paraquat cytotoxicity was also assessed. The most promising compound was further tested for its ability to increase P-gp activity ex vivo, using everted intestinal sacs from adult Wistar-Han rats. The oxygenated xanthones interacted with P-gp in vitro, increasing P-gp expression and/or activity 24 h after exposure. Additionally, after a short-incubation period, several xanthones were identified as P-gp activators, as they immediately increased P-gp activity. Moreover, some xanthones decreased PQ cytotoxicity towards Caco-2 cells, an effect prevented under P-gp inhibition. Ex vivo, a significant increase in P-gp activity was observed in the presence of OX6, which was selectively blocked by a model P-gp inhibitor, zosuquidar, confirming the in vitro results. Docking simulations between a validated P-gp model and the tested xanthones predicted these interactions, and these compounds also fitted onto previously described P-gp induction and activation pharmacophores. In conclusion, the in vitro, ex vivo, and in silico results suggest the potential of some of the oxygenated xanthones in the modulation of P-gp, disclosing new perspectives in the therapeutics of intoxications by P-gp substrates.

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

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.

Sign in / Sign up

Export Citation Format

Share Document