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Journal of Pharmaceutical Sciences May 2022Multi-drug resistance P-glycoprotein (P-gp/MDR1) is one of the most clinically relevant ABC transporters, highly enriched at the blood-brain barrier (BBB) with a broad...
Multi-drug resistance P-glycoprotein (P-gp/MDR1) is one of the most clinically relevant ABC transporters, highly enriched at the blood-brain barrier (BBB) with a broad substrate spectrum including therapeutic drugs and metabolic waste products. Altered P-gp transport function has been implicated in multi-drug resistance and in the pathogenesis and progression of neurological diseases. Recent studies have shown that P-gp expression is modulated by micro-RNAs in peripheral organs. Particularly, miR-27a-3p has been shown to play a critical role in the regulation of P-gp in multi-drug resistant cancer cells. In brain disorders, altered levels of miR-27a-3p were reported in several diseases associated with alterations in P-gp expression at the BBB. However, effect of altered miR-27a-3p expression on P-gp expression at the BBB remains to be determined. In this study, we investigated the role of miR-27a-3p in the regulation of P-gp expression and activity at the brain endothelium. Levels of miR-27a-3p were modulated by mimic and inhibitor transfection in an in-vitro model of human brain endothelial hCMEC/D3 cells. Effect of miR-27a-3p modulation on P-gp expression and activity was examined and the underlying regulatory mechanisms explored. Our results showed that transfection of hCMEC/D3 cells with miR-27a-3p mimic induces expression and activity of P-gp while miR-27a-3p inhibition exerted opposite effects. Mechanistic studies revealed that miR-27a-3p regulates P-gp by mediating Glycogen Synthase Kinase 3 Beta (GSK3ß) inhibition and activating Wnt/ß-catenin signaling. These findings shed light on miR-27a-3p/GSK3ß/ß-catenin as a novel axis that could be exploited to modulate P-gp efflux activity at the brain endothelium and help improving CNS diseases treatment or brain protection.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Brain; Catenins; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Endothelium; Humans; MicroRNAs
PubMed: 34695419
DOI: 10.1016/j.xphs.2021.10.021 -
International Journal of Molecular... Nov 2022Opioids are widely used in cancer and non-cancer pain management. However, many transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp, ABCB1/MDR1),... (Review)
Review
Opioids are widely used in cancer and non-cancer pain management. However, many transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp, ABCB1/MDR1), may impair their delivery to the brain, thus leading to opioid tolerance. Nonetheless, opioids may regulate P-gp expression, thus altering the transport of other compounds, namely chemotherapeutic agents, resulting in pharmacoresistance. Other kinds of painkillers (e.g., acetaminophen, dexamethasone) and adjuvant drugs used for neuropathic pain may act as P-gp substrates and modulate its expression, thus making pain management challenging. Inflammatory conditions are also believed to upregulate P-gp. The role of P-gp in drug-drug interactions is currently under investigation, since many P-gp substrates may also act as substrates for the cytochrome P450 enzymes, which metabolize a wide range of xenobiotics and endobiotics. Genetic variability of the ABCB1/MDR1 gene may be accountable for inter-individual variation in opioid-induced analgesia. P-gp also plays a role in the management of opioid-induced adverse effects, such as constipation. Peripherally acting mu-opioid receptors antagonists (PAMORAs), such as naloxegol and naldemedine, are substrates of P-gp, which prevent their penetration in the central nervous system. In our review, we explore the interactions between P-gp and opioidergic drugs, with their implications in clinical practice.
Topics: Humans; Analgesics; Analgesics, Opioid; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Tolerance; Pain Management; Palliative Care
PubMed: 36430602
DOI: 10.3390/ijms232214125 -
BioMed Research International 2015The efficient noninvasive treatment of neurodegenerative disorders is often constrained by reduced permeation of therapeutic agents into the central nervous system... (Review)
Review
The efficient noninvasive treatment of neurodegenerative disorders is often constrained by reduced permeation of therapeutic agents into the central nervous system (CNS). A vast majority of bioactive agents do not readily permeate into the brain tissue due to the existence of the blood-brain barrier (BBB) and the associated P-glycoprotein efflux transporter. The overexpression of the MDR1 P-glycoprotein has been related to the occurrence of multidrug resistance in CNS diseases. Various research outputs have focused on overcoming the P-glycoprotein drug efflux transporter, which mainly involve its inhibition or bypassing mechanisms. Studies into neurodegenerative disorders have shown that the P-glycoprotein efflux transporter plays a vital role in the progression of schizophrenia, with a noted increase in P-glycoprotein function among schizophrenic patients, thereby reducing therapeutic outcomes. In this review, we address the hypothesis that methods employed in overcoming P-glycoprotein in cancer and other disease states at the level of the BBB and intestine may be applied to schizophrenia drug delivery system design to improve clinical efficiency of drug therapies. In addition, the current review explores polymers and drug delivery systems capable of P-gp inhibition and modulation.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antipsychotic Agents; Blood-Brain Barrier; Drug Resistance; Humans; Schizophrenia
PubMed: 26491671
DOI: 10.1155/2015/484963 -
Journal of Pharmaceutical Sciences Sep 2017Transport proteins expressed in the different barriers of the human body can have great implications on absorption, distribution, and excretion of drug compounds.... (Review)
Review
Transport proteins expressed in the different barriers of the human body can have great implications on absorption, distribution, and excretion of drug compounds. Inhibition or saturation of a transporter can potentially alter these absorbtion, distribution, metabolism and elimination properties and thereby also the pharmacokinetic profile and bioavailability of drug compounds. P-glycoprotein (P-gp, ABCB1) is an efflux transporter which is present in most of the barriers of the body, including the small intestine, the blood-brain barrier, the liver, and the kidney. In all these tissues, P-gp may mediate efflux of drug compounds and may also be a potential site for drug-drug interactions. Consequently, there is a need to be able to predict the saturation and inhibition of P-gp and other transporters in vivo. For this purpose, Michaelis-Menten steady-state analysis has been applied to estimate kinetic parameters, such as K and V, for carrier-mediated transport, whereas half-maximal inhibitor concentration (IC) and the disassociation constant for an inhibitor/P-gp complex (K) have been determined to estimate P-gp inhibition. This review addresses in vitro methods commonly used to study P-gp transport kinetics and aims at providing a critical evaluation of the application of steady-state Michaelis-Menten analysis of kinetic parameters for substrate/P-gp interactions.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Availability; Biological Transport; Blood-Brain Barrier; Drug Interactions; Humans; Kinetics; Membrane Transport Proteins
PubMed: 28438535
DOI: 10.1016/j.xphs.2017.04.022 -
Planta Medica Apr 2017This review summarizes published , animal, and clinical studies investigating the effects of green tea () extract and associated catechins on drug-metabolizing enzymes... (Review)
Review
This review summarizes published , animal, and clinical studies investigating the effects of green tea () extract and associated catechins on drug-metabolizing enzymes and drug transporters. studies suggest that green tea extract and its main catechin, (-)-epigallocatechin-3-gallate, to varying degrees, inhibit the activity of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. UGT1A1 and UGT1A4 isoforms were also inhibited by (-)-epigallocatechin-3-gallate. Animal studies suggest green tea extract and/or (-)-epigallocatechin-3-gallate significantly increase the bioavailability of diltazem, verapamil, tamoxifen simvastatin, 5-fluorouracil, and nicardipine. Conversely, green tea extract and/or (-)-epigallocatechin-3-gallate reduce the bioavailability of quetiapine, sunitinib, clozapine, and nadolol. Of the few clinical studies available for review, it appears neither green tea extract nor (-)-epigallocatechin-3-gallate inhibit any major cytochrome P450 enzyme. Regarding drug transporters, studies indicate P-glycoprotein, organic anion transporting polypeptide 1A1, organic anion transporting polypeptide 1B1, organic anion transporting polypeptide 1B3, organic anion transporting polypeptide 2B1, organic cation transporter 1, organic cation transporter 2, multidrug and toxin extrusion 1, and multidrug and toxin extrusion 2-K are potentially inhibited by green tea extract. A clinical study indicates the organic anion transporting polypeptide 1A1 transporter is inhibited by (-)-epigallocatechin-3-gallate while P-glycoprotein is unaffected. In conclusion, the ingestion of green tea extract or its associated catechins is not expected to result in clinically significant influences on major cytochrome P450 or uridine 5'-diphospho-glucuronosyltransferase enzyme substrates or drugs serving as substrates of P-glycoprotein. However, some caution is advised in the consumption of significant amounts of green tea beverages or green tea extract in patients prescribed known substrates of organic anion transporting polypeptide, particularly those with a narrow therapeutic index.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Availability; Biological Transport; Camellia sinensis; Catechin; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Organic Anion Transporters; Tea
PubMed: 28118673
DOI: 10.1055/s-0043-100934 -
Expert Opinion on Drug Metabolism &... Jan 2020: ATP-binding cassette (ABC) transporters, especially P-glycoprotein (P-gp), and various metabolic enzymes, in particular, CYP3A, expressed in the small intestine... (Review)
Review
: ATP-binding cassette (ABC) transporters, especially P-glycoprotein (P-gp), and various metabolic enzymes, in particular, CYP3A, expressed in the small intestine cooperatively limit the absorption of orally administered P-gp substrate drugs. The expression and/or function of intestinal P-gp, however, is easily modulated by various factors.: Through extensive literature searches primarily utilizing PubMed, the authors reviewed factors that may cause inter- or intra-individual variations of the pharmacokinetics of orally administered P-gp substrate drugs due to the modulation of intestinal P-gp expression/function. The information on P-gp modulating factors can help to develop safer and more reliable oral formulations and pharmacotherapy.: In clinical pharmacotherapy with orally administered P-gp substrate drugs, the pharmacological action may exhibit a large interindividual variation among patients. Factors modulating intestinal P-gp expression/function listed here include: circadian rhythm (or drug dosing time), drug-drug interactions, formulation/excipients (vehicle, nonionic surfactants), food/supplements, gene polymorphism, obesity, colorectal carcinomas, diarrhea, hepatic failure, inflammation, inflammatory bowel disease, ischemia/reperfusion, organ transplant, renal failure, and others. We will discuss the methods for reducing the effect of modulated intestinal P-gp function on the pharmacokinetics of orally administered P-gp substrate drugs to achieve safer and more reliable oral formulations and pharmacotherapy.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Administration, Oral; Animals; Cytochrome P-450 CYP3A; Drug Interactions; Humans; Intestinal Absorption; Intestinal Mucosa; Pharmaceutical Preparations
PubMed: 31821048
DOI: 10.1080/17425255.2020.1701653 -
Natural Product Research Mar 2023Euphorbia factor L1 (EFL1, ) is a natural tri-ester of 6,17-epoxylathyrol with cancer multidrug resistance (MDR) reversal activity. Several EFL1 derivatives (-) were...
Euphorbia factor L1 (EFL1, ) is a natural tri-ester of 6,17-epoxylathyrol with cancer multidrug resistance (MDR) reversal activity. Several EFL1 derivatives (-) were prepared by chemical and microbial transformations and their ability to inhibit P-glycoprotein (P-gp) activity was estimated. Six de-acylated derivatives (-) were obtained through base-hydrolysis of , and the base-catalysed hydrolysis KOH and NaOH yielded different hydrolysed products of . Two biotransformed products (-) were directly obtained microbial transformation of , and was also formed by microbial conversion of the hydrolysed product . The P-gp modulation of - was assessed by a zebrafish model. The substrate and its biotransformed product as the tri-esters of lathyranes possessed the highest P-gp inhibitory activity with IC values of 34.97 and 15.50 µM, respectively, through down-regulating P-gp expression at the protein level rather than at MDR1 mRNA level.
Topics: Animals; Zebrafish; ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Multiple; Diterpenes; Drug Resistance, Neoplasm; Euphorbia
PubMed: 35776104
DOI: 10.1080/14786419.2022.2095379 -
Biomedical Papers of the Medical... Sep 2015P-glycoprotein (P-gp/MDR1), a member of the ATP-binding cassette (ABC) transporters super family, encoded by the ABCB1/MDR1 gene, is one of suggested respiratory tract... (Review)
Review
BACKGROUND
P-glycoprotein (P-gp/MDR1), a member of the ATP-binding cassette (ABC) transporters super family, encoded by the ABCB1/MDR1 gene, is one of suggested respiratory tract protection components, found in various tissues with a barrier function, such as tracheobronchial epithelium and lung parenchyma. As an ATP-dependent pump, P-gp extrudes lipophilic particles out of cells and acts as a gatekeeper against numerous xenobiotics, with a protective role in mediating DNA damage, secretion of toxic compounds, apoptosis and the immune response. Therefore, a presence of MDR1 polymorphisms and altered P-gp expression may be important for pathogenesis of reduced lung inflammatory response on cigarette smoke exposure, as well as for the severity of chronic obstructive pulmonary disease and lung cancer pathogenesis and treatment efficacy.
METHODS AND RESULTS
We have analyzed data available from experimental and clinical studies performed to establish the role of MDR1 polymorphisms, especially the 3435C>T variation, and P-gp expression in pathogenesis and clinical outcome of human respiratory diseases.
CONCLUSIONS
Although there are indications that altered expression of P-gp and/or polymorphisms of MDR1 gene play an important role in respiratory diseases pathogenesis and treatment, their exact role and relevance are insufficiently investigated, with exception of certain chemotherapeutic agents' efficacy in lung cancer treatment. Further research in this field, including bigger series of patients, is necessary for better understanding of respiratory diseases' pathogenesis and treatment.
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; DNA; Gene Expression Regulation; Genetic Predisposition to Disease; Humans; Polymorphism, Genetic; Respiratory Tract Diseases
PubMed: 24993742
DOI: 10.5507/bp.2014.032 -
Chemical Biology & Drug Design Mar 2019P-glycoprotein (P-gp) is a multidrug resistance (MDR) transporter with unknown structural details. This macromolecule is normally responsible for extruding xenobiotics...
P-glycoprotein (P-gp) is a multidrug resistance (MDR) transporter with unknown structural details. This macromolecule is normally responsible for extruding xenobiotics from normal cells. Overexpression of P-gp in tumor cells is a major obstacle in cancer chemotherapy. In this study, human 3D model of P-gp was built by homology modeling based on mouse P-gp crystallographic structure and stabilized through 1 ns molecular dynamics (MD) simulation. Stabilized human P-gp structure was used for flexible docking of 80 drugs into the putative active site of P-gp. Accordingly, digoxin, itraconazole, risperidone, ketoconazole, prazosin, verapamil, cyclosporine A, and ranitidine were selected for further in vitro assay. Subsequently, cell-based P-gp inhibition assay was performed on Caco-2 cells while Tc-methoxyisobutylisonitrile (MIBI) was used as a P-gp efflux substrate for calculating IC50 values. Results of the Tc-MIBI uptake in drug-treated Caco-2 cells were in agreement with the previously reported activities. This study for the first time described the relation between molecular dynamics and flexible docking with cellular experiments using Tc-MIBI radiotracer for evaluation of potencies of P-gp inhibitors. Finally, results showed that our radiotracer-cell-based assay is an accurate and fast screening tool for detecting P-gp inhibitors and non-inhibitors in drug development process.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Binding Sites; Caco-2 Cells; Drug Resistance, Neoplasm; Humans; Inhibitory Concentration 50; Molecular Docking Simulation; Organotechnetium Compounds; Protein Structure, Tertiary; Radiopharmaceuticals
PubMed: 30270513
DOI: 10.1111/cbdd.13411 -
Biochimica Et Biophysica Acta.... Apr 2018ABC (ATP binding cassette) transporters, ubiquitous in all kingdoms of life, carry out essential substrate transport reactions across cell membranes. Their transmembrane... (Comparative Study)
Comparative Study Review
ABC (ATP binding cassette) transporters, ubiquitous in all kingdoms of life, carry out essential substrate transport reactions across cell membranes. Their transmembrane domains bind and translocate substrates and are connected to a pair of nucleotide binding domains, which bind and hydrolyze ATP to energize import or export of substrates. Over four decades of investigations into ABC transporters have revealed numerous details from atomic-level structural insights to their functional and physiological roles. Despite all these advances, a comprehensive understanding of the mechanistic principles of ABC transporter function remains elusive. The human multidrug resistance transporter ABCB1, also referred to as P-glycoprotein (P-gp), is one of the most intensively studied ABC exporters. Using ABCB1 as the reference point, we aim to compare the dominating mechanistic models of substrate transport and ATP hydrolysis for ABC exporters and to highlight the experimental and computational evidence in their support. In particular, we point out in silico studies that enhance and complement available biochemical data. "This article is part of a Special Issue entitled: Beyond the Structure-Function Horizon of Membrane Proteins edited by Ute Hellmich, Rupak Doshi and Benjamin McIlwain."
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Adenosine Triphosphate; Animals; Biological Transport; Humans; Models, Biological; Molecular Dynamics Simulation; Protein Binding; Protein Conformation
PubMed: 29097275
DOI: 10.1016/j.bbamem.2017.10.028