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European Archives of Psychiatry and... Aug 2006The MDR1 gene product P-glycoprotein is an ATP-dependent efflux pump, which transports its substrates out of cells. It is not only expressed in tumor cells, but also in... (Review)
Review
The MDR1 gene product P-glycoprotein is an ATP-dependent efflux pump, which transports its substrates out of cells. It is not only expressed in tumor cells, but also in cells of normal tissues. For example, it is located in the apical membrane of enterocytes, in endothelial cells forming the blood-brain and blood-testis barriers and in the apical membrane of placental syncytiotrophoblast. Since P-glycoprotein transports a wide range of drugs (e.g. antidepressants, antiepileptics, HIV protease inhibitors, cyclosporine, digoxin), its location in these tissues limits bioavailability of orally administered drugs and prevents entry of xenobiotics into the brain, testis and the fetus. Recent data highlight the role of intestinal P-glycoprotein for drug interactions (e.g. digoxin), of P-glycoprotein expressed in the blood-brain barrier for drug penetration into the CNS (e.g. loperamide, amitriptyline), the role of pharmacological inhibition of P-glycoprotein function to increases drug concentrations in sanctuary sites (e.g. for the HI virus) and for the potential role of MDR1 polymorphisms for P-glycoprotein expression, drug disposition, adverse drug reactions and disease risk. Taken together, active drug transport is now considered as an important additional mechanism limiting drug accumulation in multiple tissues including the CNS.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Biological Transport; Blood-Brain Barrier; Central Nervous System Diseases; Humans
PubMed: 16783494
DOI: 10.1007/s00406-006-0662-6 -
Novartis Foundation Symposium 2002The human P glycoprotein (Pgp; MDR1) is an ATP-driven transporter for hydrophobic drugs and causes multidrug resistance in cancer. Our knowledge related to the... (Comparative Study)
Comparative Study Review
The human P glycoprotein (Pgp; MDR1) is an ATP-driven transporter for hydrophobic drugs and causes multidrug resistance in cancer. Our knowledge related to the mechanistic details of the ATP hydrolytic cycle of MDR1 has recently significantly progressed due to studies on the formation of a catalytic intermediate (occluded nucleotide state). According to the most accepted current model, both catalytic sites in MDR1 are active and ATP is hydrolysed alternatively within the two sites. ATP hydrolysis at one site triggers conformational changes within the protein resulting in drug transport, while hydrolysis of a second ATP molecule (at the other site) is required for resetting the initial ('high-affinity binding') conformation. The two active sites act in a cooperative manner and experiments support a model where the two ATP binding cassette (ABC) domains form a coupled catalytic machinery. Although no high resolution structure is available as yet, some relevant structural information can be deduced from crystal structures obtained for several bacterial ABC units, and the recently solved bacterial ABC-ABC dimer crystal structures may provide the basis for a better understanding of the intramolecular cross-talk between the two catalytic sites. As intramolecular interactions between various domains of Pgp/MDR1 are essential in regulating both the ATPase and transport activity, compounds perturbing these interactions may interfere with the function of the transporter. Such compounds, as well as various substrate analogues may be useful in modulating multidrug resistance in cancer.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphate; Archaeal Proteins; Bacterial Proteins; Binding Sites; Biological Transport, Active; Catalysis; Dimerization; Drug Resistance, Multiple; Humans; Hydrolysis; Hydrophobic and Hydrophilic Interactions; Models, Molecular; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 11990782
DOI: No ID Found -
Drug Metabolism Reviews 2002
Review
Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Genes, MDR; Humans; Pharmaceutical Preparations; Terminology as Topic; Tissue Distribution
PubMed: 11996011
DOI: 10.1081/dmr-120001389 -
Naunyn-Schmiedeberg's Archives of... Apr 2019Mitragynine is a major component isolated from Mitragyna speciosa Korth or kratom, a medicinal plant known for its opiate-like and euphoric properties. Multiple toxicity...
Mitragynine is a major component isolated from Mitragyna speciosa Korth or kratom, a medicinal plant known for its opiate-like and euphoric properties. Multiple toxicity and fatal cases involving mitragynine or kratom have been reported but the underlying causes remain unclear. P-glycoprotein (P-gp) is a multidrug transporter which modulates the pharmacokinetics of xenobiotics and plays a key role in mediating drug-drug interactions. This study investigated the effects of mitragynine on P-gp transport activity, mRNA, and protein expression in Caco-2 cells using molecular docking, bidirectional assay, RT-qPCR, Western blot analysis, and immunocytochemistry techniques, respectively. Molecular docking simulation revealed that mitragynine interacts with important residues at the nucleotide binding domain (NBD) site of the P-gp structure but not with the residues from the substrate binding site. This was consistent with subsequent experimental work as mitragynine exhibited low permeability across the cell monolayer but inhibited digoxin transport at 10 μM, similar to quinidine. The reduction of P-gp activity in vitro was further contributed by the downregulation of mRNA and protein expression of P-gp. In summary, mitragynine is likely a P-gp inhibitor in vitro but not a substrate. Hence, concurrent administration of mitragynine-containing kratom products with psychoactive drugs which are P-gp substrates may lead to clinically significant toxicity. Further clinical study to prove this point is needed.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Caco-2 Cells; Cell Membrane; Digoxin; Humans; Molecular Docking Simulation; RNA, Messenger; Secologanin Tryptamine Alkaloids
PubMed: 30604191
DOI: 10.1007/s00210-018-01605-y -
Mini Reviews in Medicinal Chemistry Feb 2005The aim of the present review is to summarize recent progress in identifying substrate binding domains of P-glycoprotein by photoaffinity labeling. Preferred substrate... (Review)
Review
The aim of the present review is to summarize recent progress in identifying substrate binding domains of P-glycoprotein by photoaffinity labeling. Preferred substrate binding regions have been identified using a number of photoaffinity ligands, including anthracyclines, the quinazoline iodoarylazidoprazosine (IAAP), dihydropyridines, taxanes and propafenones. These studies allowed identification of protein regions, which are involved in ligand interaction.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Binding Sites; Humans; Ligands; Photoaffinity Labels
PubMed: 15720286
DOI: 10.2174/1389557053402738 -
Current Topics in Medicinal Chemistry 2010In recent years, several PET tracers for monitoring the activity and expression of P-gp at the BBB have been tested. P-gp substrates such as [(11)C]verapamil and... (Review)
Review
In recent years, several PET tracers for monitoring the activity and expression of P-gp at the BBB have been tested. P-gp substrates such as [(11)C]verapamil and [(11)C]loperamide can be employed to visualize P-gp activity, but they display a moderate baseline uptake in the brain and formation of radiolabeled metabolites which hamper the interpretation of PET data. P-gp inhibitors such as [(11)C]elacridar, [(11)C]laniquidar and [(11)C]tariquidar have been tested to investigate P-gp expression and the results need further investigation. Recently, we developed MC18, MC266 and MC80, that have been characterized as an inhibitor, substrate and inducer of P-gp both by in vitro assays and in the everted gut sac method. These compounds have been radiolabelled with (11)C and been evaluated in vivo. In the present review, we compare the outcome of biological in vitro assays and the corresponding in vivo PET data for the P-gp inhibitors [(11)C]MC18 and [(11)C]elacridar, the P-gp substrates [(11)C]MC266 and [(11)C]verapamil, the P-gp inducer [(11)C]MC80 and the P-gp modulator cyclosporin A. Since a satisfactory overlap was found comparing in vivo results and the corresponding in vitro findings, the proposed biological in vitro assays could be predictive for the in vivo PET data of novel radiotracers. PET tracers could be employed for various purposes: radiolabeled P-gp inhibitors to monitor decreased expression of P-gp at the BBB in neurodegenerative disorders such as Alzheimer's and Parkinson's disease; and radiolabeled P-gp substrates with a high baseline uptake to monitor increased expression of P-gp in epileptic foci.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Biological Transport; Humans; Isotope Labeling; Positron-Emission Tomography
PubMed: 20645922
DOI: 10.2174/156802610792928022 -
The New England Journal of Medicine Nov 1995
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Humans; Necrosis; Neoplasms
PubMed: 7477126
DOI: 10.1056/NEJM199511233332111 -
Expert Opinion on Drug Delivery Jan 2014P-glycoprotein (P-gp) is a multi-specific efflux transporter belonging to ATP-binding cassette (ABC) transporter family, encoded by the ABCB1 gene, which significantly... (Review)
Review
INTRODUCTION
P-glycoprotein (P-gp) is a multi-specific efflux transporter belonging to ATP-binding cassette (ABC) transporter family, encoded by the ABCB1 gene, which significantly impacts the pharmacokinetics as well as multidrug resistance of anticancer drugs.
AREAS COVERED
This review explores how human P-gp transporters modulate the pharmacokinetics of anticancer drugs and emerging strategies to modulate their function. The key findings in direct modulation by various P-gp inhibitors on pharmacokinetics of various anticancer P-gp substrates are described. The role of pharmaceutical excipients as P-gp inhibitor with the focus on the recent development in novel drug delivery systems to modulate pharmacokinetics of anticancer drugs is also outlined.
EXPERT OPINION
The concomitant use of anticancer P-gp substrate and P-gp inhibitor is an effective and safe way to enhance the bioavailability of anticancer drugs. The poor bioavailability and toxicity of anticancer drugs limit their therapeutic efficacy. These characteristics can be improved by using various nanocarriers which exhibited a high potential to bypass this efflux protein. The best combination of P-gp inhibitor and substrate anticancer drug in a single nanocarrier formulation is a future challenge and is still probably some years away from the marketplace.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Drug Delivery Systems; Humans
PubMed: 24295039
DOI: 10.1517/17425247.2014.865014 -
Clinical and Experimental Nephrology Feb 2012Although corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) are widely used in the treatment of various systemic autoimmune diseases... (Review)
Review
Although corticosteroids, immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) are widely used in the treatment of various systemic autoimmune diseases such as systemic lupus erythematosus (SLE), we often experience patients with systemic autoimmune diseases who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, is known to play a pivotal role in the acquisition of drug resistance to chemotherapy in malignancy. However, the relevance of MDR-1 and P-gp to resting and activated lymphocytes, which are the major target in the treatment of systemic autoimmune diseases, remains unclear. Studies from our laboratories found surface expression of P-gp on peripheral lymphocytes in patients with SLE and a significant correlation between the expression level and disease activity. Such expression is induced not only by genotoxic stresses but also by various stimuli including cytokines, resulting in active efflux of drugs from the cytoplasm of lymphocytes, resulting in drug-resistance and high disease activity. However, the use of both P-gp antagonists (e.g., cyclosporine) and inhibition of P-gp synthesis with intensive immunosuppressive therapy successfully reduces the efflux of corticosteroids from lymphocytes in vitro, suggesting that P-gp antagonists and P-gp synthesis inhibitors could be used to overcome drug-resistance in vivo and improve outcome. In conclusion, lymphocytes activated by various stimuli in patients with highly active disease apparently acquire MDR-1-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. The expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable target to combat drug resistance in patients with active systemic autoimmune diseases.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antirheumatic Agents; Autoimmune Diseases; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphocytes
PubMed: 21847519
DOI: 10.1007/s10157-011-0520-3 -
Current Cancer Drug Targets 2014Scientific community is striving to understand the role of P-glycoprotein (P-gp) in drug discovery programs due to its impact on pharmacokinetic and multi-drug... (Review)
Review
Scientific community is striving to understand the role of P-glycoprotein (P-gp) in drug discovery programs due to its impact on pharmacokinetic and multi-drug resistance (MDR) of anticancer drugs. A number of efforts to resolve the crystal structure and understanding the mechanism of P-gp mediated efflux have been made. Several generations of Pgp inhibitors have been developed to tackle this multi-specific efflux protein. Unfortunately, these inhibitors lack selectivity, exhibit poor solubility and severe pharmacokinetic interactions restricting their clinical use. The nanocarrier drug delivery systems (NDDS) are receiving increasing attention for P-gp modulating activity of pharmaceutical excipients which are used in their fabrication. In addition, NDDS can enhance the solubility and exhibited ability to bypass P-gp mediated efflux. The co-formulation of P-gp inhibitors and substrate anticancer drugs in single drug delivery system offers the advantage of bypassing P-gp mediated drug efflux as well as inhibiting the P-gp. Moreover, severe pharmacokinetic interactions between P-gp inhibitor and substrate anticancer drugs could be avoided by using this strategy. In this article we describe the co-formulation strategies using nanocarriers for modulation of pharmacokinetics as well as multi-drug resistance of anticancer drugs along with the challenges in this area.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Chemistry, Pharmaceutical; Drug Carriers; Humans; Nanotechnology; Neoplasms
PubMed: 24720364
DOI: 10.2174/1568009614666140407112034