Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two monoclonal antibodies of F (ab')2 form, MRK 16 and MRK 20 that recognize P-glycoprotein and P85 kD protein respectively, were useful to detect multidrug resistant cells in human lymphoma, leukemia and gastrointestinal cancer cell lines. They were classified into 4 groups: Group I (4 cell lines) was insensitive to vinca alkaloids, anthracyclines, etoposide (VP-16) and actinomycin-D (ACT-D), and reactive to MRK 16 and MRL 20. Group II (2 cell lines) was insensitive to vincristine (VCR), but not reactive to both antibodies. Group III (3 cell lines) was insensitive to anthracyclines and VP-16, but sensitive to vinca alkaloids and ACT-D, and reactive to MRK 20 but not to MRK 16. Group IV (all other cell lines) was sensitive to these drugs, and not reactive to both antibodies. MRK 16 detects P-glycoprotein-associated multidrug resistance (MDR), while MRK 20 detects P 85kd-associated novel MDR. These monoclonal antibodies were useful for detection of MDR cells in clinical samples.
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PMID:[Detection of multidrug resistant cells in human malignant diseases by monoclonal antibodies and strategy to eradicate resistant malignant cells]. 256 3

Pluronic block copolymers have been previously reported to increase the delivery of agents to the brain [Kabanov et al. (1992) J. Controlled Release 22, 141-158]. In the present study, primary cultured bovine brain microvessel endothelial cells (BBMEC) were used as an in vitro model of the blood-brain barrier to examine the membrane interactions of Pluronic P85 (P85) and potential mechanisms for drug absorption. At concentrations below the critical micelle concentration (cmc), P85 enhanced the accumulation of the fluorescent probe rhodamine 123 (R123) in BBMEC through inhibition of P-glycoprotein (P-gp)-mediated drug efflux. The effects of P85 on the cellular accumulation of R123 were also observed in KBv cells (P-gp positive) but not in human umbilical vein endothelial cells (P-gp negative). In contrast to the effects with P85 below the cmc, the enhanced absorption of R123 observed with Pluronic micelles was transient and not dependent on P-gp. A transient increase in R123 accumulation was observed in both P-gp positive cells (brain microvessel endothelial cells and KBv) and P-gp negative cells (human umbilical vein endothelial cells). Therefore, it appears that P85 affects the absorption of drugs in brain microvessel endothelial cells through (1) inhibition of the P-gp-mediated drug efflux at low concentrations of the copolymer and (2) increased vesicular transport at higher concentrations of the copolymer. Furthermore, both interactions of P85 with the brain endothelial cells appear to be energy-dependent as demonstrated by the inhibitory effects of the metabolic inhibitor 2-deoxyglucose.
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PMID:Interactions of pluronic block copolymers with brain microvessel endothelial cells: evidence of two potential pathways for drug absorption. 932 27

Drug delivery across the blood-brain barrier is limited by several mechanisms. One important mechanism is drug efflux, mediated by several transport proteins, including P-glycoprotein. The goal of this work was to examine the effect of a novel drug delivery system, Pluronic block copolymer P85, on P-glycoprotein-mediated efflux from the brain using in vitro and in vivo methods. The hypothesis was that specific Pluronic copolymer systems enhance drug delivery to the central nervous system through the inhibition of P-glycoprotein. The effect of P85 on the cellular accumulation and transport of digoxin, a model P-glycoprotein substrate, was examined in porcine kidney epithelial cells (LLC-PK1) transfected with the human MDR1 gene. The effect of P85 on the directional flux across an in vitro BBB was also characterized. In vivo brain distribution studies were accomplished using wild-type and P-glycoprotein knockout mice. Pluronic increased the cellular accumulation of digoxin 3-fold in LLC-PK1 cells and 5-fold in the LLC-PK1-MDR1-transfected cells. Similar effects were observed for a prototypical P-glycoprotein substrate rhodamine-123. P85 treatment decreased the basolateral-to-apical and increased the apical-to-basolateral digoxin flux across LLC-PK1-MDR1 cell monolayers, and analogous results were observed with the in vitro BBB monolayers. The coadministration of 1% P85 with radiolabeled digoxin in wild-type mice increased the brain penetration of digoxin 3-fold and the digoxin level in the P85-treated wild-type mice was similar to that observed in the P-glycoprotein-deficient animals. These data indicate that Pluronic P85 can enhance the delivery of digoxin to the brain through the inhibition of the P-glycoprotein-mediated efflux mechanism.
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PMID:Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies. 1116 Jun 43

Pluronic block copolymer, P85, inhibits the P-glycoprotein (Pgp) drug efflux system and increases the permeability of a broad spectrum of drugs in the blood-brain barrier (BBB). This study examines the mechanisms by which P85 inhibits Pgp using bovine brain microvessel endothelial cells (BBMEC) as an in vitro model of the BBB. The hypothesis was that simultaneous alterations in intracellular ATP levels and membrane fluidization in BBMEC monolayers by P85 results in inhibition of the drug efflux system. The methods included the use of 1) standard Pgp substrate rhodamine 123 to assay the Pgp efflux system in BBMEC, 2) luciferin/luciferase assay for ATP intracellular levels, and 3) 1,6-diphenyl-1,3,5-hexatriene for membrane microviscosity. Using 3H-labeled P85 and fluorescein-labeled P85 for confocal microscopy, this study suggests that P85 accumulates in the cells and intracellular organelles such as the mitochondria where it can interfere with metabolic processes. Following exposure of BBMEC to P85, the ATP levels were depleted, and microviscosity of the cell membranes was decreased. Furthermore, P85 treatment decreased Pgp ATPase activity in membranes expressing human Pgp. A combination of experiments examining the kinetics, concentration dependence, and directionality of P85 effects on Pgp-mediated efflux in BBMEC monolayers suggests that both energy depletion (decreasing ATP pool available for Pgp) and membrane fluidization (inhibiting Pgp ATPase activity) are critical factors contributing to the activity of the block copolymer in the BBB.
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PMID:Mechanism of pluronic effect on P-glycoprotein efflux system in blood-brain barrier: contributions of energy depletion and membrane fluidization. 1160 58

This paper, for the first time, demonstrates that exposure of cells to the poly(ethylene oxide)-poly(propylene oxide) block copolymer, Pluronic P85, results in a substantial decrease in ATP levels selectively in MDR cells. Cells expressing high levels of functional P-glycoprotein (MCF-7/ADR, KBv; LLC-MDR1; Caco-2, bovine brain microvessel endothelial cells [BBMECs]) are highly responsive to Pluronic treatment, while cells with low levels of P-glycoprotein expression (MCF-7, KB, LLC-PK1, human umbilical vein endothelial cells [HUVECs] C2C12 myoblasts) are much less responsive to such treatment. Cytotoxicity studies suggest that Pluronic acts as a chemosensitizer and potentiates cytotoxic effects of doxorubicin in MDR cells. The ability of Pluronic to inhibit P-glycoprotein and sensitize MDR cells appears to be a result of ATP depletion. Because many mechanisms of drug resistance are energy dependent, a successful strategy for treating MDR cancer could be based on selective energy depletion in MDR cells. Therefore, the finding of the energy-depleting effects of Pluronic P85, in combination with its sensitization effects is of considerable theoretical and practical significance.
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PMID:Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion. 1174 44

Peptide-based drug development is a rapidly growing field within pharmaceutical research. Nevertheless, peptides have found limited clinical use due to several physiological and pathological factors. Pluronic block copolymers represent a growing technology with the potential to enhance efficacy of peptide therapeutics. This investigation assesses Pluronic P85 (P85) and its potential to enhance opioid peptide analgesia. Two opioid peptides, [D-Pen(2),D-Pen(5)]-enkephalin (DPDPE) and biphalin, were examined as to the benefits of P85 coadministration, above (1.0%) and below (0.01%) the critical micelle concentration, with morphine as a nonpeptide control. P85 was examined in vitro to assess blood-brain barrier uptake in association with P-glycoprotein effect, DPDPE and morphine being P-glycoprotein substrates. P85 coadministration with DPDPE and biphalin showed increased (p < 0.01) analgesia with both 0.01 and 1.0% P85. Morphine showed increased (p < 0.01) analgesia with 0.01% P85 only. This increase in analgesia is due to both an increase in peak effect, as well as a prolongation of effect. P85 increased cellular uptake of (125)I-DPDPE and [(3)H]morphine at 0.01% (p < 0.01) and 1.0% (p < 0.01 and p < 0.05, respectively). Cyclosporin-A coadministration with (125)I-DPDPE and [(3)H]morphine increased cellular uptake (p < 0.01 and p < 0.05, respectively). (125)I-DPDPE and [(3)H]morphine coadministered with 0.01% P85 and cyclosporin-A increased cellular uptake compared with control (p < 0.01) and compared with cyclosporin-A coadministration without P85 (p < 0.01 and p < 0.05, respectively). This indicates that, in addition to P-gp inhibition, 0.01% P85 increased (125)I-DPDPE and [(3)H]morphine uptake. In our examination, we determined that P85 enhanced the analgesic profile of biphalin, DPDPE, and morphine, both above and below the critical micelle concentration.
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PMID:Pluronic p85 block copolymer enhances opioid peptide analgesia. 1238 63

Pluronic block copolymer P85 was shown to inhibit the P-glycoprotein (Pgp) drug efflux system and to increase the permeability of a broad spectrum of drugs in the blood-brain barrier (BBB). However, there is an entire series of Pluronics varying in lengths of propylene oxide and ethylene oxide and overall lipophilicity. This study identifies those structural characteristics of Pluronics required for maximal impact on drug efflux transporter activity in bovine brain microvessel endothelial cells (BBMECs). Using a wide range of block copolymers, differing in hydrophilic-lipophilic balance (HLB), this study shows that lipophilic Pluronics with intermediate length of propylene oxide block (from 30 to 60 units) and HLB <20 are the most effective at inhibiting Pgp efflux in BBMECs. The methods used included 1) cellular accumulation studies with the Pgp substrate rhodamine 123 in BBMECs to assess Pgp activity; 2) luciferin/luciferase ATP assay to evaluate changes in cellular ATP; 3) 1,6-diphenyl-1,3,5-hexatriene membrane microviscosity studies to determine alterations in membrane fluidity; and 4) Pgp ATPase assays using human Pgp-expressing membranes. Pluronics with intermediate lipophilic properties showed the strongest fluidization effect on the cell membranes along with the most efficient reduction of intracellular ATP synthesis in BBMEC monolayers. The relationship between the structure of Pluronic block copolymers and their biological response-modifying effects in BBMECs are useful for determining formulations with maximal efficacy for increasing BBB permeability.
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PMID:Optimal structure requirements for pluronic block copolymers in modifying P-glycoprotein drug efflux transporter activity in bovine brain microvessel endothelial cells. 1253 42

The potential inhibitory effects of 3 excipients (polyethylene glycol [PEG] 400, Pluronic P85, and vitamin E d-a-tocopheryl polyethylene glycol 1000 succinate [TPGS]) on the P-glycoprotein (P-gp) -mediated efflux of digoxin (DIG) and cytochrome P450 3A (CYP3A) -mediated metabolism of verapamil (VRP) have been examined in an in vitro permeability model. Experiments were conducted utilizing rat jejunal tissue mounted in diffusion chambers and included assessment of the serosal to mucosal (s to m) transport of DIG and the formation of norverapamil (NOR) during the mucosal to serosal transport of VRP, as measures of P-gp efflux and CYP3A metabolism, respectively. The presence of PEG at 1%, 5%, and 20% (wt/vol) reduced both the s to m flux of DIG (by 47%, 57%, and 64%, respectively, when compared to control) and the metabolism of VRP (by 54%, 78%, and 100%) in a concentration-dependent manner. P85 (0.1% wt/vol) significantly reduced s to m DIG flux by 47% and inhibited VRP metabolism by 42%. TPGS had insignificant effects on both metabolism and efflux at a concentration of 0.01% (wt/vol). The P-gp inhibitory effects of PEG and P85 were evident regardless of whether the excipient was added to the mucosal side, the serosal side, or both sides of the tissue. The current data suggest that inclusion of PEG and P85 as solubilizing agents during in vitro permeability assessment may have a significant impact on both drug metabolism and efflux processes. These compounds appear to exert their effects on P-gp primarily via direct transporter inhibition - or indirectly, through effects on buffer osmolarity, membrane fluidity, and/or mitochondrial toxicity and subsequent adenosine triphosphate (ATP) depletion.
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PMID:An in vitro examination of the impact of polyethylene glycol 400, Pluronic P85, and vitamin E d-alpha-tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein efflux and enterocyte-based metabolism in excised rat intestine. 1264 11

Pluronic block copolymers are known to sensitize multidrug resistant (MDR) tumors with respect to various anticancer agents, particularly, anthracycline antibiotics. After completion of the Phase I clinical trial, the formulation containing doxorubicin and Pluronic, SP1049C, is undergoing Phase II clinical trials. Studies of the mechanism of the sensitization effect of Pluronic suggested an essential role of ATP depletion in MDR tumors by the block copolymer. The ATP depletion phenomenon was further examined using a panel of cells with varying levels of expression of P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs). Cell responses were characterized in terms of EC(50), a concentration of Pluronic P85 resulting in a 50% decrease in ATP intracellular levels. These studies suggested that the cells displaying high responses in ATP depletion with EC(50)<0.01% were strongly sensitized by the block copolymer resulting in drastic increases of doxorubicin cytotoxic activity (over 100-fold). In contrast, the less responsive cells with EC(50)>ca. 0.02% were practically not sensitized by the block copolymer. The responses of the cells to P85 in ATP depletion studies correlated with the levels of expression of the drug efflux transport proteins, primarily Pgp. This provided initial evidence that Pgp may be useful as a gene expression marker for predicting potential responses to doxorubicin/Pluronic formulation in chemotherapy of cancer.
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PMID:An essential relationship between ATP depletion and chemosensitizing activity of Pluronic block copolymers. 1293 39

This article reviews recent advances in our understanding of the structure, drug interaction mechanism, and substrate molecular requirements of P-glycoprotein (P-gp) and its emerging crucial role in drug disposition and the modulation of drug interaction. In view of its wide localization in normal tissues, the broad variety of structurally and functionally unrelated substrates of P-gp, and its ATP-dependent outward-oriented transport, P-gp actively participates in intestinal secretion, blood-tissue barriers, and biliary and renal excretions for many exogenous substrates, and also performs a protective role to prevent entry of xenobiotics. Moreover, the importance of P-gp-mediated drug interactions in clinical practice can hardly be underestimated, since it may result in severe side effects, such as digitalis drug interaction. Polymorphism or single nucleotide polymorphism (SNP) associated with P-gp may exert a significant effect on the pharmacokinetic behavior of its substrates, a fact which has major clinical implications and suggests careful dose adjustment for individual treatment. Moreover, dietary components and pharmaceutical excipients may modulate P-gp activity, and as a result affect in vivo drug disposition and therapeutic efficacy; examples include grapefruit juice, Pluronic P85, PEG 300, etc. In summary, it should be emphasized that P-gp is an integral component in the process of drug discovery, development strategy,
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PMID:Multidrug resistance P-glycoprotein: crucial significance in drug disposition and interaction. 1470 47


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