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)

The kidney plays an important role in the elimination of numerous hydrophilic xenobiotics, including drugs, toxins, and endogenous compounds. It has developed high-capacity transport systems to prevent urinary loss of filtered nutrients, as well as electrolytes, and simultaneously to facilitate tubular secretion of a wide range of organic ions. Transport systems for organic anions and cations are primarily involved in the secretion of drugs in renal tubules. The identification and characterization of organic anion and cation transporters have been progressing at the molecular level. To date, many members of the organic anion transporter, organic cation transporter, and organic anion-transporting polypeptide families have been found to mediate the transport of diverse organic ions. It has also been suggested that ATP-dependent primary active transporters such as MDR1/P-glycoprotein and the multidrug resistance-associated protein family function as efflux pumps of renal tubular cells for more hydrophobic molecules and anionic conjugates. Tubular reabsorption of peptide-like drugs such as beta-lactam antibiotics across the brush-border membranes appears to be mediated by two distinct H+/peptide cotransporters: PEPT1 and PEPT2. Renal disposition of drugs occurs through interaction with these diverse secretory and absorptive transporters in renal tubules. Studies of the functional characteristics, such as substrate specificity and transport mechanisms, and of the localization of drug transporters could provide information regarding the cellular network involved in renal handling of drugs. Detailed information concerning molecular and cellular aspects of drug transporters expressed in the kidney has facilitated studies of the mechanisms underlying renal disposition as well as transporter-mediated drug interactions.
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PMID:Renal tubular drug transporters. 1655 67

Transmembrane transport of endogenous as well as synthetic opioid peptides is a critical determinant of pharmacokinetics and biologic efficacy of these peptides. This transport process influences the distribution of opioid peptides across the blood-brain barrier and their elimination from the body. A multitude of transport systems that recognize opioid peptides as substrates have been characterized at the functional level, and these transport systems are expressed differentially at different sites in the body. Many of these transport systems have been identified at the molecular level. These include the H(+)-coupled peptide transporters PEPT1 and PEPT2, the adenosine triphosphate-dependent efflux transporters P-glycoprotein and multidrug resistance-related protein 2, and several members of the organic anion-transporting polypeptide gene family. There are however many additional transport systems that are known to transport opioid peptides but their molecular identities still remain unknown.
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PMID:Transport systems for opioid peptides in mammalian tissues. 1659 37

Disposition of the lipid-lowering agent ezetimibe (EZ) and its glucuronide (GLUC), which is mainly formed by UDP-glucuronosyltransferase (UGT) 1A1, is influenced by the intestinal efflux transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) 2. To evaluate the role of Mrp2 in overall disposition and pharmacodynamic effects of EZ, wild-type and Mrp2-deficient (TR-negative) Lewis.1W rats (eight males each) fed with a cholesterol-enriched diet were orally treated with 5 mg/kg EZ for 14 days. EZ and GLUC in serum, urine, and feces, and cholesterol, campesterol, and sitosterol in serum, were assayed using liquid chromatography (LC)-tandem mass spectrometry and LC-mass spectrometry methods, respectively. Gene expression of Bsep (bile salt exporting pump), multidrug resistance (Mdr) 1a, Mdr1b, Mrp2, Mrp3, Ntcp (sodium taurocholate co-transporting polypeptide), organic anion transporting polypeptides (Oatp) 1, 2, 4, and Ugt1a1 was quantified in several tissues using real-time reverse transcription-polymerase chain reaction. Mrp2 deficiency resulted in lower serum levels and fecal excretion of EZ (1.4 +/- 0.4 versus 3.1 +/- 1.1 ng/ml; 115 +/- 48 versus 361 +/- 102 microg/day, both p < 0.01), whereas serum concentrations of GLUC were manyfold increased compared with wild type (196 +/- 76 versus 23 +/- 25 ng/ml; p < 0.01), associated with elevated renal excretion and decreased intestinal clearance (7.8 +/- 3.1 versus 0.4 +/- 0.4 microg/day, p < 0.01; 0.3 +/- 0.3 versus 15 +/- 17 ml/min; p < 0.05). The sterol-lowering effect of EZ was reduced in correlation to EZ serum levels (cholesterol: r = 0.449, p = 0.093; campesterol: r = 0.717, p = 0.003; sitosterol: r = 0.507, p = 0.054), whereas GLUC was inversely correlated (r = -0.743, p = 0.002; r =-0.768, p = 0.001; r =-0.634, p = 0.011). Disposition of EZ may have been additionally influenced by hepatic P-gp, Mrp3, and Ugt1a1, which were expressed significantly higher in Mrp2-deficient rats. Mrp2 deficiency in rats is associated with decreased sterol-lowering effect of ezetimibe, obviously caused by lower intestinal clearance of the glucuronide and decreased enterosystemic and enterohepatic recycling of the parent ezetimibe to the intestinal Niemann-Pick C 1-like 1 sterol-uptake compartment.
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PMID:Disposition and sterol-lowering effect of ezetimibe in multidrug resistance-associated protein 2-deficient rats. 1677 39

Fexofenadine, a substrate of P-glycoprotein and an organic anion transporter polypeptide, is commonly used to assess P-glycoprotein activity in vivo. The purpose of this study was to elucidate the pharmacokinetics of each fexofenadine enantiomer. After a single oral dose of racemic fexofenadine (60 mg), the plasma and urine concentrations of fexofenadine enantiomers were measured over the course of 24 h in six healthy subjects. The mean plasma concentration of R(+)-fexofenadine was higher than that of S(-)-fexofenadine. The area under the plasma concentration-time curve (AUC(0-infinity)) and the maximum plasma concentration (C(max)) of R(+)-fexofenadine were significantly greater than those of the S(-)-enantiomer (P = 0.0018 and 0.0028, respectively). The R/S ratios of AUC and C(max) of fexofenadine were 1.75 and 1.63, respectively. The oral clearance and renal clearance of S(-)-fexofenadine were significantly greater than that of R(+)-fexofenadine (P = 0.0074 and 0.0036). On the other hand, the stereoselective metabolism of fexofenadine using recombinant CYP3A4 was investigated; however, fexofenadine enantiomers were not metabolized by CYP3A4. Fexofenadine is transported by both P-glycoprotein and OATP and is not metabolized by intestinal CYP3A. Our findings suggest that the affinity of P-glycoprotein for S(-)-fexofenadine is greater than its affinity for the R(+)-enantiomer. Thus, P-glycoprotein is likely to have chiral discriminatory abilities.
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PMID:Pharmacokinetics of fexofenadine enantiomers in healthy subjects. 1723 Apr 98

In humans, indirect evidence suggests that hypoxia reduces the rate of biotransformation of drugs cleared by cytochrome P450 (P450) subfamilies CYP1A, 2B, and 2C. The aim of this study was to assess whether acute moderate hypoxia modulates the expression of CYP2B4, 2C5, and 2C16 in vivo, and to determine whether the changes in hepatic P450 are conveyed by serum mediators. Moreover, because hypoxia increases the expression of P-glycoprotein in vitro, we examined whether in vivo acute moderate hypoxia modulates the expression of several membrane transporters in the liver. Rabbits and rats were exposed to a fractional concentration of oxygen of 8% for 48 h to generate a stable arterial partial pressure of O2 of 34 +/- 1 mm Hg. Compared with rabbits breathing room air, hypoxia in rabbits reduced the amount of CYP1A1, 1A2, 2B4, 2C5, and 2C16 proteins and increased the expression of CYP3A6. Sera of rabbits with hypoxia were fractionated by size exclusion chromatography, the fractions were tested for their ability to modify the expression of P450 isoforms, and serum mediators were identified through neutralization experiments. The serum mediators responsible for the down-regulation of P450 isoforms were interferon-gamma, interleukin-1beta (IL-1beta), and IL-2. In vivo, in rats, hypoxia increased the mRNA and protein expression of P-glycoprotein but did not affect the mRNA of breast cancer resistance protein and organic anion-transporting polypeptide 2. It is concluded that in vivo, hypoxia down-regulates rabbit hepatic CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulates CYP3A6. CYP3A11 and P-glycoprotein were up-regulated in the livers of hypoxic rats.
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PMID:Animal models of acute moderate hypoxia are associated with a down-regulation of CYP1A1, 1A2, 2B4, 2C5, and 2C16 and up-regulation of CYP3A6 and P-glycoprotein in liver. 1730 24

The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.
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PMID:A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance. 1748 74

Freshly isolated hepatocytes are widely accepted as the "gold standard" for providing reliable data on drug uptake across the sinusoidal (basolateral) membrane. However, the suitability of freshly isolated hepatocytes in suspension to assess efflux by canalicular (apical) proteins or predict biliary excretion in the intact organ is unclear. After collagenase digestion, hepatocytes rapidly lose polarity, but localization of canalicular transport proteins in the first few hours after isolation has not been well characterized. In this study, immunostaining and confocal microscopy have provided, for the first time, a detailed examination of canalicular transport protein localization in freshly isolated rat hepatocytes fixed within 1 h of isolation and in cells cultured for 1 h. Organic anion transporting polypeptide 1a1 (Oatp1a1) was expressed in all hepatocytes and distributed evenly across the basolateral membrane; there was no evidence for colocalization of Oatp1a1 with P-glycoprotein (P-gp) or multidrug resistance-associated protein 2 (Mrp2). In contrast, P-gp and Mrp2 expression was lower than Oatp1a1 and confined to junctions between adjacent cells, intracellular compartments, and "legacy" network structures at or near the cell surface. P-gp and Mrp2 staining was more predominant in regions adjacent to former canalicular spaces, identified by zonula occludens-1 staining. Functional analysis of rat hepatocytes cultured for 1 h demonstrated that the fluorescent anion and Mrp2 substrate, 5-(and-6)-carboxy-2',7'-dichlorofluorescein (CDF), accumulated in cellular compartments; compartmental accumulation of CDF was sensitive to (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid (MK571, Mrp inhibitor) and was not observed in hepatocytes isolated from Mrp2-deficient rats. Drug efflux from freshly isolated hepatocytes as an estimate of apical efflux/biliary excretion would give an inaccurate assessment of true apical elimination and, as such, should not be used to make in vivo extrapolations.
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PMID:Localization of P-gp (Abcb1) and Mrp2 (Abcc2) in freshly isolated rat hepatocytes. 1795 25

A robust screen for compound interaction with P-glycoprotein (P-gp) has some obvious requirements, such as a cell line expressing P-gp and a probe substrate that is transported solely by P-gp and passive permeability. It is actually difficult to prove that a particular probe substrate interacts only with P-gp in the chosen cell line. Using a confluent monolayer of MDCKII-hMDR1 cells, we have determined the elementary rate constants for the P-gp efflux of amprenavir, digoxin, loperamide, and quinidine. For amprenavir and quinidine, transport was fitted with just P-gp and passive permeability. For digoxin and loperamide, fitting required a basolateral transporter (p < 0.01), which was inhibited by the P-gp inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). This means that when digoxin is used as a probe substrate and a compound is shown to inhibit digoxin flux, it could be that the inhibition occurs at the basolateral transporter rather than at P-gp. Digoxin basolateral>apical efflux also required an apical importer (p < 0.05). We propose that amprenavir and quinidine are robust probe substrates for assessing P-gp interactions using the MDCKII-hMDR1 confluent cell monolayer. Usage of another cell line, e.g., LLC-hMDR1 or Caco-2, would require the same kinetic validation to ensure that the probe substrate interacts only with P-gp. Attempts to identify the additional digoxin and loperamide transporters using a wide range of substrates/inhibitors of known epithelial transporters (organic cation transporters, organic anion transporters, organic ion-transporting polypeptide, uric acid transporter, or multidrug resistance-associated protein) failed to inhibit the digoxin or loperamide transport through their basolateral transporter.
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PMID:Kinetic identification of membrane transporters that assist P-glycoprotein-mediated transport of digoxin and loperamide through a confluent monolayer of MDCKII-hMDR1 cells. 1796 33

Tyroservatide (YSV) is an active, low-molecular-weight polypeptide that has been shown to have antitumor effects on human hepatocellular carcinoma BEL-7402 cells in vitro and in vivo. Multi-drug resistance (MDR) represents a major obstacle to the success of cancer chemotherapy. To enhance the chemosensitivity of tumor cells, attention has been focused on MDR modulators. In this study, we evaluated the reversal effect of YSV on MDR, and explored its mechanism of action in vitro. Administration of YSV reversed the multi-drug resistance of human hepatocellular carcinoma BEL-7402/5-FU cells significantly. The intracellular accumulation of doxorubicin and Rhodamine-123 (Rh123) were increased, which implied that the function of the P-glycoprotein (P-gp) efflux pump was inhibited by YSV. Moreover, the mRNA and protein expression of multi-drug resistance gene (MDR1) were also decreased by YSV. We observe that lung-resistance protein (LRP) and multi-drug resistance-associated protein (MRP1) each contribute to MDR in BEL-7402/5-FU cells as well. The mRNA and protein expression of LRP were decreased by YSV. No significant change was observed in mRNA expression of MRP1. However, we observe that the MRP1 protein level was reduced after treatment with YSV. These data demonstrate that YSV effectively reverses MDR in BEL-7402/5-FU cells, and that its mechanism of action is associated with the down-regulation of MDR1, MRP1 and LRP expression, as well as the inhibition of P-gp function.
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PMID:Reversal effect of tyroservatide (YSV) tripeptide on multi-drug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5-FU. 1853 71

Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.
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PMID:Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. 1856 12


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