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International Journal of Molecular... Nov 2022Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood-brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette... (Review)
Review
Maintenance of the tightly regulated homeostatic environment of the brain is facilitated by the blood-brain barrier (BBB). P-glycoprotein (P-gp), an ATP-binding cassette transporter, is expressed on the luminal surface of the endothelial cells in the BBB, and actively exports a wide variety of substrates to limit exposure of the vulnerable brain environment to waste buildup and neurotoxic compounds. Downregulation of P-gp expression and activity at the BBB have been reported with ageing and in neurodegenerative diseases. Upregulation of P-gp at the BBB contributes to poor therapeutic outcomes due to altered pharmacokinetics of CNS-acting drugs. The regulation of P-gp is highly complex, but unravelling the mechanisms involved may help the development of novel and nuanced strategies to modulate P-gp expression for therapeutic benefit. This review summarises the current understanding of P-gp regulation in the brain, encompassing the transcriptional, post-transcriptional and post-translational mechanisms that have been identified to affect P-gp expression and transport activity.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Endothelial Cells; ATP Binding Cassette Transporter, Subfamily B; Brain; Blood-Brain Barrier; Central Nervous System Agents
PubMed: 36498995
DOI: 10.3390/ijms232314667 -
Clinical Pharmacokinetics 2003P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells.... (Review)
Review
P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen. Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Transport, Active; Biotransformation; Drug Interactions; Humans; Intestinal Absorption; Pharmacokinetics; Species Specificity; Tissue Distribution
PubMed: 12489979
DOI: 10.2165/00003088-200342010-00003 -
Expert Opinion on Drug Metabolism &... Apr 2021: P-glycoprotein (P-gp) is an important efflux pump responsible for the extruding of many endogenous and exogenous substances out of the cells. P-gp can be modulated by... (Review)
Review
: P-glycoprotein (P-gp) is an important efflux pump responsible for the extruding of many endogenous and exogenous substances out of the cells. P-gp can be modulated by different molecules - including xanthone derivatives - to surpass the multidrug resistance (MDR) phenomenon through P-gp inhibition, or to serve as an antidotal strategy in intoxication scenarios through P-gp induction/activation.: This review provides a perspective on P-gp modulators, with particular focus on xanthonic derivatives, highlighting their ability to modulate P-gp expression and/or activity, and the potential impact of these effects on the pharmacokinetics, pharmacodynamics and toxicity of P-gp substrates.: Xanthones, of natural or synthetic origin, are able to modulate P-gp, interfering with its protein synthesis or with its mechanism of action, by decreasing or increasing its efflux capacity. These modulatory effects make the xanthonic scaffold a promising source of new derivatives with therapeutic potential. However, the mechanisms beyond the xanthones-mediated P-gp modulation and the chemical characteristics that make them more potent P-gp inhibitors or inducers/activators are still understudied. Furthermore, a new window of opportunity exists in the neuropathologies field, where xanthonic derivatives with potential to modulate P-gp should be further explored to optimize the prevention/treatment of brain pathologies.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Availability; Brain Diseases; Drug Interactions; Humans; Pharmaceutical Preparations; Xanthones
PubMed: 33283552
DOI: 10.1080/17425255.2021.1861247 -
Autoimmunity Reviews Jul 2015P-glycoprotein (Pgp) is a transmembrane protein of 170 kD encoded by the multidrug resistance 1 (MDR-1) gene, localized on chromosome 7. More than 50 polymorphisms of... (Review)
Review
P-glycoprotein (Pgp) is a transmembrane protein of 170 kD encoded by the multidrug resistance 1 (MDR-1) gene, localized on chromosome 7. More than 50 polymorphisms of the MDR-1 gene have been described; a subset of these has been shown to play a pathophysiological role in the development of inflammatory bowel disease, femoral head osteonecrosis induced by steroids, lung cancer and renal epithelial tumors. Polymorphisms that have a protective effect on the development of conditions such as Parkinson disease have also been identified. P-glycoprotein belongs to the adenosine triphosphate binding cassette transporter superfamily and its structure comprises a chain of approximately 1280 aminoacid residues with an N-C terminal structure, arranged as 2 homologous halves, each of which has 6 transmembrane segments, with a total of 12 segments with 2 cytoplasmic nucleotide binding domains. Many cytokines like interleukin 2 and tumor necrosis factor alpha increase Pgp expression and activity. Pgp functions as an efflux pump for a variety of toxins in order to protect particular organs and tissues as the central nervous system. Pgp transports a variety of substrates including glucocorticoids while other drugs such as tacrolimus and cyclosporine A act as modulators of this protein. The most widely used method to measure Pgp activity is flow cytometry using naturally fluorescent substrates such as anthracyclines or rhodamine 123. The study of drug resistance and its association to Pgp began with the study of resistance to chemotherapy in the treatment of cancer and antiretroviral therapy for human immunodeficiency virus; however, the role of Pgp in the treatment of systemic lupus erythematosus, rheumatoid arthritis and psoriatic arthritis has been a focus of study lately and has emerged as an important mechanism by which treatment failure occurs. The present review analyzes the role of Pgp in these autoimmune diseases.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Autoimmune Diseases; Humans; Polymorphism, Genetic; Rheumatic Diseases; Substrate Specificity
PubMed: 25712147
DOI: 10.1016/j.autrev.2015.02.006 -
Expert Opinion on Therapeutic Patents Jun 2019P-glycoprotein is a complex ATP-ase transporter involved in physiological and pathological functions. In particular, it is involved in the onset of multidrug resistance... (Review)
Review
INTRODUCTION
P-glycoprotein is a complex ATP-ase transporter involved in physiological and pathological functions. In particular, it is involved in the onset of multidrug resistance in cancer, in ocular disease, Chronic Rhinosinusitis, CNS diseases such as Alzheimer, Parkinson, and epilepsy. One of the aims of clinicians and pharmacologists is to monitor P-gp activity through the inhibitors and to use its activity and/or expression in physiological barriers for the early diagnosis of several pathologies. Considering P-glycoprotein activity, several substrates have been characterized but the challenge is to design '' P-glycoprotein inhibitors.
AREAS COVERED
P-glycoprotein inhibitors display a large spectrum of activities. Here the contents of patents focused on the role of P-glycoprotein inhibitor in modulating MDR in cancer, in bioavailability, in ocular disease and Chronic Rhinosinusitis are reported.
EXPERT OPINION
The use of P-glycoprotein inhibitor , or in coadministration with therapeutic agents, for ocular disease, and Chronic Rhinosinusitis is promising and could be suggested for additional trials. By contrast, the bioavailability of the coadministrated drugs, increased by P-glycoprotein inhibitor, deserves a wider discussion, in particular on the pharmacokinetic aspect of both P-glycoprotein inhibitor and the coadministered drug.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Biological Availability; Drug Design; Drug Interactions; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Neoplasms; Patents as Topic
PubMed: 31079547
DOI: 10.1080/13543776.2019.1618273 -
Life Sciences Dec 2018P-glycoprotein (P-gp) is a member of ATP-binding cassette (ABC) superfamily which extrudes chemotherapeutic agents out of the cell. Suppression of this efflux activity... (Review)
Review
P-glycoprotein (P-gp) is a member of ATP-binding cassette (ABC) superfamily which extrudes chemotherapeutic agents out of the cell. Suppression of this efflux activity has been the subject of numerous attempts to develop P-gp inhibitors. The aim of this review is to present up-to-date information on the structural and functional aspects of P-gp and its known inhibitors. The data presented also provide some information on drug discovery approaches for candidate P-gp inhibitors. Nucleotide-binding domains (NBDs) and drug-binding domains (DBDs) have been extensively studied to gain more information about P-gp inhibition and it looks that the ATPase activity of this pump has been the most attractive target for designing inhibitors. Hydrophobic and π-π (aromatic) interactions between P-gp binding domains and inhibitors are dominant intermolecular forces that have been reported in many studies using different methods. Many synthetic and natural products have been found to possess inhibitory or modulatory effects on drug transporter proteins. Log P value is an important factor in studying these inhibitors and has a crucial role on absorption, distribution, metabolism, and excretion (ADME) properties of candidate P-gp inhibitors.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Acridines; Antineoplastic Agents; Binding Sites; Biological Products; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Lipid Bilayers; Molecular Targeted Therapy; Piperidines; Protein Conformation; Quinolines; Tetrahydroisoquinolines
PubMed: 30449449
DOI: 10.1016/j.lfs.2018.10.048 -
Current Medicinal Chemistry 2019The P-glycoprotein is an efflux transporter that expels substances out of the cells and has an important impact on the pharmacokinetic and pharmacodynamic properties of... (Review)
Review
The P-glycoprotein is an efflux transporter that expels substances out of the cells and has an important impact on the pharmacokinetic and pharmacodynamic properties of drugs. The study of the interactions between ligands and the P-glycoprotein has implications in the design of Central Nervous System drugs and their transport across the blood-brain barrier. Moreover, since the P-glycoprotein is overexpressed in some types of cancers, the protein is responsible for expelling the drug therapies from the cells, and hence, for drug resistance. In this review, we describe different P-glycoprotein binding sites reported for substrates, inhibitors and modulators, and focus on molecular docking studies that provide useful information about drugs and P-glycoprotein interactions. Docking in crystallized structures and homology models showed potential in the detection of the binding site and key residues responsible for ligand recognition. Moreover, virtual screening through molecular docking discriminates P-glycoprotein ligands from decoys. We also discuss challenges and limitations of molecular docking simulations applied to this particular protein. Computational structure-based approaches are very helpful in the study of novel ligands that interact with the P-glycoprotein and provide insights to understand the P-glycoprotein molecular mechanism of action.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Binding Sites; Humans; Ligands; Molecular Docking Simulation; Organic Chemicals; Protein Binding
PubMed: 29189117
DOI: 10.2174/0929867325666171129121924 -
Journal of Ethnopharmacology Jun 2012P-glycoprotein belongs to the family of ATP-binding cassette (ABC) transporters. It functions in cellular detoxification, pumping a wide range of xenobiotic compounds,... (Review)
Review
P-glycoprotein belongs to the family of ATP-binding cassette (ABC) transporters. It functions in cellular detoxification, pumping a wide range of xenobiotic compounds, including anticancer drugs out of the cell. In cancerous cells, P-glycoprotein confers resistance to a broad spectrum of anticancer agents, a phenomenon termed multidrug resistance. An attractive strategy for overcoming multidrug resistance is to block the transport function of P-glycoprotein and thus increase intracellular concentrations of anticancer drugs to lethal levels. Efforts to identify P-glycoprotein inhibitors have led to numerous candidates, none of which have passed clinical trials with cancer patients due to their high toxicity. The search for naturally inhibitory products from traditional Chinese medicine may be more promising because natural products are frequently less toxic than chemically synthesized substances. In this review, we give an overview of molecular and clinical aspects of P-glycoprotein and multidrug resistance in the context of cancer as well as Chinese herbs and phytochemicals showing inhibitory activity towards P-glycoprotein.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents, Phytogenic; Drug Resistance, Neoplasm; Drugs, Chinese Herbal; Humans; Neoplasms; Plants, Medicinal
PubMed: 21963565
DOI: 10.1016/j.jep.2011.08.053 -
Pharmacological Research Oct 2003Drug efflux pumps like P-glycoprotein (P-gp) and multidrug resistance (MDR) proteins were recognized to possess functional role in determining the pharmacokinetics of... (Review)
Review
Drug efflux pumps like P-glycoprotein (P-gp) and multidrug resistance (MDR) proteins were recognized to possess functional role in determining the pharmacokinetics of drugs administered by peroral as well as parenteral route. Advancements in molecular biology, to some extent, had revealed the structure, localization and functional role of P-glycoprotein and its mechanism of drug efflux. Broad substrate recognition by this protein and clinical implications of its inhibition has revolutionized cancer chemotherapy leading to design and development of novel P-glycoprotein inhibitors. In the recent times, the application of these inhibitors in improving peroral drug delivery has gained special interest. Inhibition of P-glycoprotein improves intestinal absorption and tissue distribution while reducing the substrate metabolism and its elimination. Eventually, various screening methodologies have been developed for determining the activity of P-glycoprotein, kinetics of drug transport and identification of substrates and inhibitors. In the present review, techniques used for screening P-glycoprotein inhibitors and the scope of these inhibitors in optimizing peroral drug absorption and pharmacokinetics are discussed along with a brief introduction to P-glycoprotein, its physiological function and active role in extrusion of drugs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Availability; Biological Transport; Drug Evaluation, Preclinical; Intestinal Absorption; Models, Biological
PubMed: 12902205
DOI: 10.1016/s1043-6618(03)00158-0 -
Journal of Medicinal Chemistry Jun 2018Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for... (Review)
Review
Multidrug resistance (MDR) is a major cause of failure in cancer chemotherapy. P-glycoprotein (P-gp), a promiscuous drug efflux pump, has been extensively studied for its association with MDR due to overexpression in cancer cells. Several P-gp inhibitors or modulators have been investigated in clinical trials in hope of circumventing MDR, with only limited success. Alternative strategies are actively pursued, such as the modification of existing drugs, development of new drugs, or combination of novel drug delivery agents to evade P-gp-dependent efflux. Despite the importance and numerous studies, these efforts have mostly been undertaken without a priori knowledge of how drugs interact with P-gp at the molecular level. This review highlights and discusses progress toward and challenges impeding drug development for inhibiting or evading P-gp in the context of our improved understanding of the structural basis and mechanism of P-gp-mediated MDR.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Protein Conformation
PubMed: 29251920
DOI: 10.1021/acs.jmedchem.7b01457