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Molecules (Basel, Switzerland) May 2019P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with...
P-glycoprotein (P-gp) is a transmembrane protein that actively transports a wide variety of chemically diverse compounds out of the cell. It is highly associated with the ADMET (absorption, distribution, metabolism, excretion and toxicity) properties of drugs/drug candidates and contributes to decreasing toxicity by eliminating compounds from cells, thereby preventing intracellular accumulation. Therefore, in the drug discovery and toxicological assessment process it is advisable to pay attention to whether a compound under development could be transported by P-gp or not. In this study, an in silico multiclass classification model capable of predicting the probability of a compound to interact with P-gp was developed using a counter-propagation artificial neural network (CP ANN) based on a set of 2D molecular descriptors, as well as an extensive dataset of 2512 compounds (1178 P-gp inhibitors, 477 P-gp substrates and 857 P-gp non-active compounds). The model provided a good classification performance, producing non error rate (NER) values of 0.93 for the training set and 0.85 for the test set, while the average precision (AvPr) was 0.93 for the training set and 0.87 for the test set. An external validation set of 385 compounds was used to challenge the model's performance. On the external validation set the NER and AvPr values were 0.70 for both indices. We believe that this in silico classifier could be effectively used as a reliable virtual screening tool for identifying potential P-gp ligands.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Drug Discovery; Humans; Mice; Models, Molecular; Models, Theoretical; Neural Networks, Computer
PubMed: 31130601
DOI: 10.3390/molecules24102006 -
Bioorganic & Medicinal Chemistry Letters Nov 2012The requirement to cross a biological membrane can be a complex process especially if multidrug transporters such as P-gp must be considered. Drug partitioning into the... (Review)
Review
The requirement to cross a biological membrane can be a complex process especially if multidrug transporters such as P-gp must be considered. Drug partitioning into the lipid membrane and efflux by P-gp are tightly coupled processes wherein H-bonding interactions play a key role. All H-bond donors and acceptors are not equal in terms of the strength of the H-bonds that they form, hence it is important to consider their relative strength. Using various examples from literature, we illustrate the benefits of considering the relative strengths of individual H-bonds and introducing intramolecular H-bonds to increase membrane permeability and/or decrease P-gp efflux.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Hydrogen Bonding; Molecular Structure; Permeability
PubMed: 23006604
DOI: 10.1016/j.bmcl.2012.08.059 -
Food and Chemical Toxicology : An... Dec 2020The drug transporter P-glycoprotein (P-gp) is often investigated in drug-interaction studies because the activity is modulated by a wide variety of xenobiotics including...
The drug transporter P-glycoprotein (P-gp) is often investigated in drug-interaction studies because the activity is modulated by a wide variety of xenobiotics including drugs, herbal products, and food components. In this study, we tested six common arylsulfonate food dyes-allura red, carmoisine, ponceau 4R, quinolone yellow, sunset yellow, and tartrazine-as activators and inhibitors of P-gp activity in vitro. The dyes were studied as P-gp activators by measuring ATPase activity in P-gp-expressing membranes. Compared to verapamil, a known activator of P-gp, the six food dyes showed no stimulatory activity. The potential for these six food dyes to act as P-gp inhibitors was tested in an intracellular efflux assay with P-gp-expressing cells. Compared to GF120918, a known P-gp inhibitor, there was no inhibitory activity for these six food dyes. The six food dyes tested do not interact with P-gp in vitro and, therefore, are unlikely cause clinical drug-food dye interactions. Further investigation is necessary to determine whether these food dyes could interact with other drug transporters.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adenosine Triphosphatases; Biological Transport; Drug Interactions; Food Coloring Agents; Food-Drug Interactions; Humans; Verapamil
PubMed: 33011351
DOI: 10.1016/j.fct.2020.111785 -
Journal of Pharmacological Sciences 2014In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood... (Review)
Review
In clinical pharmacotherapy, therapeutic benefits and adverse effects of medicines differ substantially between individuals and are often determined by their blood levels. Critical regulators influencing the pharmacokinetics and pharmacodynamics of drugs include drug transporters and drug-metabolizing enzymes. Among these, we have focused on P-glycoprotein (P-gp), a drug efflux transporter. A growing body of evidence indicates that the expression and functional activity of P-gp are altered under several pathological conditions, by exposure to substrate drugs of P-gp, and by ingestion of certain foods. In this critical review, we discuss the mechanisms by which anticancer drugs, most of which are P-gp substrates, alter the expression and functional activity of P-gp in tumors and normal tissues after chronic treatment. Accumulating evidence shows that various transcription factors, in addition to epigenetic and post-translational factors, modulate P-gp expression, which alters the pharmacokinetics and pharmacological effects of drugs. Therefore, it is important to consider individual patients with regard to drug-taking history, as well as levels of P-gp expression and function, when providing clinical pharmacotherapy.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Narcotics; Substrate Specificity; Transcription Factors
PubMed: 24989947
DOI: 10.1254/jphs.14r01cr -
International Journal of Molecular... Feb 2023Acute myeloid leukemia (AML) remains an insidious neoplasm due to the percentage of patients who develop resistance to both classic chemotherapy and emerging drugs.... (Review)
Review
Acute myeloid leukemia (AML) remains an insidious neoplasm due to the percentage of patients who develop resistance to both classic chemotherapy and emerging drugs. Multidrug resistance (MDR) is a complex process determined by multiple mechanisms, and it is often caused by the overexpression of efflux pumps, the most important of which is P-glycoprotein (P-gp). This mini-review aims to examine the advantages of using natural substances as P-gp inhibitors, focusing on four molecules: phytol, curcumin, lupeol, and heptacosane, and their mechanism of action in AML.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B, Member 1; Curcumin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Leukemia, Myeloid, Acute
PubMed: 36835550
DOI: 10.3390/ijms24044140 -
PloS One 2015Multidrug efflux transporter P-glycoprotein (P-gp) is highly expressed on membrane of tumor cells and is implicated in resistance to tumor chemotherapy. HZ08 is...
BACKGROUND
Multidrug efflux transporter P-glycoprotein (P-gp) is highly expressed on membrane of tumor cells and is implicated in resistance to tumor chemotherapy. HZ08 is synthesized and studied in order to find a novel P-gp inhibitor.
METHODS
MDCK-MDR1 monolayer transport, calcein-AM P-gp inhibition and P-gp ATPase assays were used to confirm the P-gp inhibition capability of HZ08. Furthermore, KB-WT and KB-VCR cells were used to evaluate the P-gp inhibitory activity of HZ08 both in vitro and in vivo.
RESULTS
Results showed that HZ08 was more potent than verapamil in MDCK-MDR1 monolayer transportation model. Meanwhile, P-gp ATPase assay and calcein-AM P-gp inhibition assay confirmed that HZ08 inhibited P-gp ATPase with a calcein-AM IC50 of 2.44±0.31μM. In addition, significantly greater in vitro multidrug resistance reversing effects were observed when vincristine or paclitaxel was used in combination with 10μM HZ08 compared with 10μM verapamil. Moreover, HZ08 could significantly enhance the sensitivity of vincristine with a similar effect like verapamil in both KB-WT and KB-VCR tumor xenograft models.
CONCLUSIONS
The novel structure HZ08 could be a potent P-gp inhibitor.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Acridines; Animals; Biological Transport; Dogs; Drug Resistance, Multiple; Humans; Isoquinolines; KB Cells; Madin Darby Canine Kidney Cells; Mice; Neoplasms; Tetrahydroisoquinolines; Transplantation, Heterologous; Verapamil
PubMed: 25689592
DOI: 10.1371/journal.pone.0116886 -
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 -
Molecules (Basel, Switzerland) Nov 2023P-glycoprotein (P-gp) is a crucial membrane transporter situated on the cell's apical surface, being responsible for eliminating xenobiotics and endobiotics. P-gp... (Review)
Review
P-glycoprotein (P-gp) is a crucial membrane transporter situated on the cell's apical surface, being responsible for eliminating xenobiotics and endobiotics. P-gp modulators are compounds that can directly or indirectly affect this protein, leading to changes in its expression and function. These modulators can act as inhibitors, inducers, or activators, potentially causing drug-drug interactions (DDIs). This comprehensive review explores diverse models and techniques used to assess drug-induced P-gp modulation. We cover several approaches, including , , , and methods, with their respective strengths and limitations. Additionally, we explore the therapeutic implications of DDIs involving P-gp, with a special focus on the renal and intestinal elimination of P-gp substrates. This involves enhancing the removal of toxic substances from proximal tubular epithelial cells into the urine or increasing the transport of compounds from enterocytes into the intestinal lumen, thereby facilitating their excretion in the feces. A better understanding of these interactions, and of the distinct techniques applied for their study, will be of utmost importance for optimizing drug therapy, consequently minimizing drug-induced adverse and toxic effects.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Membrane Transport Proteins; ATP Binding Cassette Transporter, Subfamily B; Kidney; Drug Interactions
PubMed: 38005253
DOI: 10.3390/molecules28227532 -
Clinical Pharmacokinetics Feb 2016As the effect of P-glycoprotein (P-gp) transport on antidepressant delivery has been extensively evaluated using in vitro cellular and in vivo rodent models, an... (Review)
Review
As the effect of P-glycoprotein (P-gp) transport on antidepressant delivery has been extensively evaluated using in vitro cellular and in vivo rodent models, an increasing number of publications have addressed the effect of P-gp in limiting brain penetration of antidepressants and causing treatment-resistant depression in current clinical therapies. However, contradictory results have been observed in different systems. It is of vital importance to understand the potential for drug interactions related to P-gp at the blood-brain barrier (BBB), and whether coadministration of a P-gp inhibitor together with an antidepressant is a good clinical strategy for dosing of patients with treatment-resistant depression. In this review, the complicated construction of the BBB, the transport mechanisms for compounds that cross the BBB, and the basic characteristics of antidepressants are illustrated. Further, the reliability of different systems related to antidepressant brain delivery, including in vitro bidirectional transport cell lines, in vivo Mdr1 knockout mice, and chemical inhibition studies in rodents are analyzed, supporting a low possibility that P-gp affects currently marketed antidepressants when these results are extrapolated to the human BBB. These findings can also be applied to other central nervous system drugs.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antidepressive Agents; Brain; Humans
PubMed: 26293617
DOI: 10.1007/s40262-015-0310-2 -
Molecules (Basel, Switzerland) Apr 2020A new series of -bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids...
A new series of -bis(alkanol)amine aryl diesters was synthesized and studied as dual P-glycoprotein (P-gp) and carbonic anhydrase XII inhibitors (CA XII). These hybrids should be able to synergistically overcome P-gp mediated multidrug resistance (MDR) in cancer cells. It was reported that the efflux activity of P-gp could be modulated by CA XII, as the pH reduction caused by CA XII inhibition produces a significant decrease in P-gp ATPase activity. The new compounds reported here feature both P-gp and CA XII binding moieties. These hybrids contain a -bis(alkanol)amine diester scaffold found in P-glycoprotein ligands and a coumarin or benzene sulfonamide moiety to target CA XII. Many compounds displayed a dual activity against P-gp and CA XII being active in the Rhd 123 uptake test on K562/DOX cells and in the hCA XII inhibition test. On LoVo/DOX cells, that overexpress both P-gp and CA XII, some coumarin derivatives showed a high MDR reversal effect in Rhd 123 uptake and doxorubicin cytotoxicity enhancement tests. In particular, compounds and showed higher activity than verapamil and were more potent on LoVo/DOX than on K562/DOX cells overexpressing only P-gp. They can be considered as valuable candidates for selective P-gp/CA XII inhibition in MDR cancer cells.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antineoplastic Agents; Biological Transport; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Stability; Humans; K562 Cells; Molecular Structure; Structure-Activity Relationship
PubMed: 32290281
DOI: 10.3390/molecules25071748