Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, monoclonal antibody(MoAb) therapies which direct at antigens such as CD33, CD45 and GM-CSF receptors on myeloid leukemia cells have been in progress. There are three major MoAb therapies against acute myeloid leukemia(AML), which include unconjugated MoAb, MoAb conjugated with chemotherapy or toxins, and MoAb conjugated with radioisotopes. Gemtuzumab ozogamicin is consisting of an engineered human anti-CD33 antibody linked with the potent anti-tumor antibiotic calicheamicin, which is the most effective for AML. However, recent studies suggested that calicheamicin was also pumped out by multi-drug resistance(MDR) related P-glycoprotein. The combination therapy with MDR modifiers may improve the effect of gemtuzumab ozogamicin.
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PMID:[Antibody directed therapy for leukemia]. 1190 67

Multidrug resistance is frequently observed when treating cancer patients with chemotherapeutic agents. A variety of ATP binding cassette (ABC) transporters, localized in the cell membrane, cause this phenomenon by extruding a variety of chemotherapeutic agents from the tumor cells. However, the major physiological role of the multidrug transporters is the protection of our cells and tissues against xenobiotics, and these transporters play a key role in drug availability, metabolism and toxicity. Three major groups of ABC transporters are involved in multidrug resistance: the classical P-glycoprotein MDR1, the multidrug resistance associated proteins (MRP1, MRP2, and probably MRP3, MRP4 and MRP5), and the ABCG2 protein, an ABC half-transporter. All these proteins were shown to catalyze an ATP-dependent active transport of chemically unrelated compounds. MDR1 (P-glycoprotein) and ABCG2 preferentially extrude large hydrophobic, positively charged molecules, while the members of the MRP family can extrude both hydrophobic uncharged molecules and water-soluble anionic compounds. By examining the interactions of the multidrug transporters with pharmacological and toxic agents, a prediction for the cellular and tissue distribution of these compounds can be achieved. Oral bioavailability, entering the blood-brain and blood-CSF barrier, reaching the fetus through the placenta, liver and kidney secretion, cellular entry for affecting intracellular targets, are all questions, which can be addressed by basic in vitro studies on the multidrug resistance proteins. Investigation of the substrate interactions and modulation of multidrug transporters may pave the way for predictive toxicology and pharmacogenomics. Here we show that by using in vitro assay systems it is possible to measure the interactions of multidrug transporters with various drugs and toxic agents. We focus on the characterisation of the MRP1 and MRP3 proteins, their relevance in chemoresistance of cancer and in drug metabolism and toxicity.
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PMID:The role of multidrug transporters in drug availability, metabolism and toxicity. 1267 59

The introduction, in 1995, of highly active antiretroviral therapy (HAART) dramatically reduced the morbidity and mortality of HIV-infected patients. However, the brain remains a site of viral replication for HIV and thus is still an important target for antiretroviral agents. Consequently, a clear understanding of how the current anti-HIV drugs reach the CNS, and interact at the level of the blood-brain barrier and blood-CSF barrier, is important if we are to maximise viral suppression and improve clinical outcome. It would also contribute to the development of new anti-HIV drugs and the identification of transport inhibitors that could be used as adjuvant therapies. In this review we focus on the role of the blood-brain and blood-CSF barriers in the delivery of the main classes of approved anti-HIV drugs. Among these groups, the CNS distribution of the nucleoside reverse transcriptase inhibitors is the best characterised. It involves probenecid efflux transport mechanisms, which limit their brain delivery and probably their, neurological efficacy. Nevirapine and efavirenz, the commonly prescribed non-nucleoside reverse transcriptase inhibitors, can readily enter the CSF, however, it remains to be seen if a transport system is involved in their distribution. The protease inhibitors have only a limited ability to reach the CNS, with the majority of this class of drugs not even being detected in human CSF after administration. This is partly the result of their removal from the CNS by the efflux transporters; P-glycoprotein, and possibly multi-drug resistance associated protein (MRP).
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PMID:Anti-HIV drug distribution to the central nervous system. 1513 83

Exchange of compounds between blood and brain occurs at two barriers, the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). The barrier function is mainly a result of the functionality of the cerebral endothelial cells and choroidal epithelial cells, respectively. These cell types have restricted permeability due to the presence of tight junctions between the cells. Furthermore, these cells express a broad range of transporters. So far, the BBB has been viewed as the most important barrier, especially as its surface is about 3 orders of magnitude larger than that of the BCSFB. Today, there is a shift in the appreciation of the contribution of the BCSFB. In a few recent studies, it has been shown that the BCSFB expresses two types of ATP-binding cassette (ABC) transporters, being the multidrug transporters P-glycoprotein (P-gp) and the multidrug resistance-related protein 1 (MRP1). The knowledge on the function of these transporters in the BCSFB is relatively scarce, but in general, it seems that MRP1 transport is directed towards the blood side, which makes this transporter helpful in elimination of harmful compounds from the CSF. Thereby MRP1 potentially contributes to detoxification of the brain, as a whole, as it is also expressed at the level of the BBB. P-gp, however, while also functional as an efflux pump at the BBB, has an opposite transport direction at the level of the BCSFB, towards the CSF. P-gp may therefore raise the concentration of neurotoxic P-gp substrates in the CSF. Whether this will have a significant contribution to the toxicity in the regions directly exposed to the CSF (periventricular organs) remains to be determined. Specifically, in the epithelial cells of the choroid plexus of the BCSFB, P-gp and MRP1 together serve a protective role by preventing the accumulation of their overlapping and often toxic substrates. A concerted action of P-gp and MRP1 at the choroid plexus might contribute to the maintenance of the role of the BCSFB in brain homeostasis.
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PMID:Potential role of ABC transporters as a detoxification system at the blood-CSF barrier. 1538 34

Delivery to the CNS via the nasal cavity has been pursued as a means to circumvent the blood-brain barrier (BBB), yet the mechanism of drug transport across this novel route is not well understood. Hydroxyzine and triprolidine have been reported to readily reach the CNS following nasal administration, whereas no measurable amounts of chlorcyclizine or chlorpheniramine, structurally similar antihistamines, were observed in the CSF. The permeation of chlorpheniramine and chlorcyclizine in vitro across the bovine olfactory mucosa was studied to investigate the biological and physicochemical characteristics that contribute to the limited CNS disposition of these compounds following nasal administration. The submucosal to mucosal fluxes (J(s-m)) of chlorcyclizine and chlorpheniramine across the olfactory mucosa were significantly greater than the mucosal to submucosal fluxes (J(m-s)). Moreover, the submucosal-mucosal permeability of both compounds was temperature dependent and saturable. In the presence of metabolic inhibitors (ouabain and 2,4-dinitrophenol) and P-glycoprotein (P-gp)/multidrug resistance protein 1 (MRP1) inhibitors (quinidine and verapamil), the J(m-s) increased and J(s-m) decreased significantly. These results indicate that chlorpheniramine and chlorcyclizine are effluxed from the olfactory mucosa by efflux transporters such as P-gp and MRP1. Transport studies across inert polymeric membranes demonstrated that the permeability of chlorpheniramine and chlorcyclizine decreased at donor concentrations higher than 3 mM suggesting that physicochemical properties such as self-aggregation also play a role in the reduced olfactory mucosal permeability of these compounds at higher concentrations.
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PMID:Carrier mediated transport of chlorpheniramine and chlorcyclizine across bovine olfactory mucosa: implications on nose-to-brain transport. 1566 93

P-glycoprotein (P-gp) expressed on human antigen presenting cells (APC) regulates alloantigen-dependent T-cell activation, but the associated mechanisms are not well understood. Here we demonstrate that P-gp functions in IL-12-dependent monocyte differentiation into dendritic cell (DC) lineages during APC maturation, thereby regulating the capacity of myeloid-derived APCs to elicit alloimmune Th1 responses. Human CD14+ monocytes cultured in vitro in the presence of IL-4/GM-CSF differentiated into CD14(-) CD1A+ APCs of the immature DC phenotype. In contrast, P-gp blockade during differentiation inhibited CD1a induction, down-regulated CD80 expression, enhanced CD86 expression and induced CD68 expression. APCs differentiated in the presence of P-gp blockade stimulated alloimmune T-cell proliferation significantly less than controls and this effect was associated with 97% inhibition of Th1 IFN-gamma production, but preserved Th2 IL-5 secretion. MAb-mediated blockade of the P-gp transport substrate IL-12 in the course of APC differentiation also inhibited IFN-gamma production, while addition of rIL-12 to P-gp-blocked APC differentiation cultures significantly reversed this effect, demonstrating that P-gp functions in APC differentiation in part via IL-12 regulation. Our findings define a novel role for P-gp as a differentiation switch in APC maturation and resultant alloimmune Th1 responses, thereby identifying P-gp as a potential novel therapeutic target in allotransplantation.
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PMID:P-glycoprotein functions as a differentiation switch in antigen presenting cell maturation. 1708 70

The goals of this component were to discuss the potential for NeuroAIDS therapeutics. The presentations included discussions of biomarkers, pathogenic mechanisms of disease, laboratory models, and the development of adjunctive therapies for neuroinflammatory and neurodegenerative disorders with a focus on NeuroAIDS. Talks by Dana Giulian on the use of CSF biomarkers for therapeutic trial design in dementia, Howard Fox on the SIV model of NeuroAIDS, Christine Zink on minocycline and its antiretroviral activities, and Katrina L. Mealey on the means to improve drug access to the brain by regulation P-glycoprotein, rounded out the session. It was acknowledged that although a number of compounds including selegiline, nimodipine, and memantine were studied in clinical trials and showed some trends towards clinical improvement none showed significance. Drugs such as minocycline, sodium valproate, and P-glycoprotein regulators were discussed and now are being developed. Partnerships between public institutions and private companies were discussed. Multidisciplinary teams are likely required to see such research to fruition, and the developmental schemes from the molecule to the laboratory to the animal to the clinic were discussed and developed in the session.
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PMID:Biomarkers, laboratory, and animal models for the design and development of adjunctive therapies for HIV-1 dementia and other neuroinflammatory disorders. 1804 Aug 20

The objective of the present study was to examine the accuracy of using unbound brain concentration determined by a brain homogenate method (C(ub)), cerebral spinal fluid concentration (C(CSF)), and unbound plasma concentration (C(up)) as a surrogate for brain interstitial fluid concentration determined by brain microdialysis (C(m)). Nine compounds-carbamazepine, citalopram, ganciclovir, metoclopramide, N-desmethylclozapine, quinidine, risperidone, 9-hydroxyrisperidone, and thiopental-were selected, and each was administered as an intravenous bolus (up to 5 mg/kg) followed by a constant intravenous infusion (1-9 mg/kg/h) for 6 h in rats. For eight of the nine compounds, the C(ub)s were within 3-fold of their C(m); thiopental had a C(m) 4-fold of its C(ub). The C(CSF)s of eight of the nine compounds were within 3-fold of their corresponding C(m); 9-hydroxyrisperidone showed a C(CSF) 5-fold of its C(m). The C(up)s of five of the nine compounds were within 3-fold of their C(m); four compounds (ganciclovir, metoclopramide, quinidine, and 9-hydroxyrisperidone) had C(up)s 6- to 14-fold of their C(m). In conclusion, the C(ub) and C(CSF) were within 3-fold of the C(m) for the majority of the compounds tested. The C(up)s were within 3-fold of C(m) for lipophilic non-P-glycoprotein (-P-gp) substrates and greater than 3-fold of C(m) for hydrophilic or P-gp substrates. The present study indicates that the brain homogenate and cerebral spinal fluid methods may be used as surrogate methods to predict brain interstitial fluid concentrations within 3-fold of error in drug discovery and development settings.
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PMID:Unbound drug concentration in brain homogenate and cerebral spinal fluid at steady state as a surrogate for unbound concentration in brain interstitial fluid. 1911 65

P-glycoprotein (P-gp/ABCB1), multidrug resistance associated protein 1 (MRP1/ABCC1), and breast cancer resistance protein (BCRP/ABCG2) are plasma membrane efflux pumps that limit the intracellular uptake and retention of numerous lipophilic, amphipathic xeno- and endobiotics. Little is known about the neonatal and developmental expression of P-gp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2 in the human central nervous system (CNS), therefore post-mortem CNS tissue from infants born at 22 (0/7)-42 (0/7) weeks of gestation and adults was immunostained to determine their ontogeny and cellular localization. P-gp/ABCB1 immunostaining was observed in microvessel endothelial cells as early as 22 (0/7) weeks, increasing in prevalence and intensity with maturation, and later in gestation in large pyramidal neurons. MRP1/ABCC1 immunostaining was prominent early in the choroid plexus and ventricular ependyma, and noted later in large pyramidal neurons. BCRP/ABCG2 expression was limited to microvessel endothelial cells. P-gp/ABCB1, MRP1/ABCC1 and BCRP/ABCG2 in adult brain matched term newborn CNS but with more intense immunostaining. We conclude that P-gp/ABCB1, MRP1/ABCC1, and BCRP/ABCG2 are expressed in a developmental, cell specific, fashion in the human CNS. The complementary pattern of P-gp/ABCB1 and BCRP/ABCG2 at the blood-brain with MRP1/ABCC1 at the blood-CSF barriers may limit CNS uptake and retention of drugs and toxins in neonates.
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PMID:ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing human CNS. 1916 9

Brain penetration of drugs which are subject to P-glycoprotein (Pgp)-mediated efflux is attenuated, as manifested by the fact that the cerebrospinal fluid concentration (C(CSF)), a good surrogate of the unbound brain concentration (C(ub)), is lower than the unbound plasma concentration (C(up)) for Pgp substrates. In rodents, the attenuation magnitude of brain penetration by Pgp-mediated efflux has been estimated by correlating the ratio of CSF to plasma exposures (C(CSF)/C(p)) with the unbound fraction in plasma (f(u)) upon the incorporation of the in vivo or in vitro Pgp-mediated efflux ratios (ERs). In the present work, we investigated the impact of Pgp-mediated efflux on C(CSF) in monkeys. Following intravenous administration to cisterna magna ported rhesus monkeys, the CSF and plasma concentrations were determined for 25 compounds from three discovery programs. We also evaluated their f(u) in rhesus plasma and ER in human and African green monkey MDR-transfected LLC-PK1 cells. These compounds varied significantly in the f(u) (0.025-0.73), and 24 out of 25 are considered Pgp substrates based on their appreciable directional transport (ER>2). The C(CSF)/C(p) was significantly lower than the corresponding f(u) (>or=3-fold) for 16 compounds regardless of a significant correlation (R(2)=0.59, p=4 x 10(-5)) when the C(CSF)/C(p) was plotted against the f(u). When the f(u) was normalized to the ER (f(u)/ER) the correlation was improved (R(2)=0.75, p=8 x 10(-8)). More importantly, only one compound showed the C(CSF)/C(p) that exceeded 3-fold of the normalized f(u). The results suggest that the impact of Pgp-mediated efflux in monkeys, similar to the case in rodents, is reasonably reflected by the gradient between the free concentrations in plasma and in CSF. Therefore, f(u) and Pgp ER may serve as useful measurements in estimating in vivo C(CSF)/C(p) ratios in monkeys, and potentially in humans.
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PMID:Effect of P-glycoprotein-mediated efflux on cerebrospinal fluid concentrations in rhesus monkeys. 1948 Oct 60


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