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)

Vascular inflammation is well known for its ability to compromise the function of the blood--brain barrier (BBB). Whether inflammation on the parenchymal side of the barrier, such as that associated with Parkinson's-like dopamine (DA) neuron lesions, similarly disrupts BBB function, is unknown. We assessed BBB integrity by examining the leakage of FITC-labeled albumin or horseradish peroxidase from the vasculature into parenchyma in animals exposed to the DA neurotoxin 6-hydroxydopamine (6OHDA). Unilateral injections of 6OHDA into the striatum or the medial forebrain bundle produced increased leakage in the ipsilateral substantia nigra and striatum 10 and 34 days following 6OHDA. Microglia were markedly activated and DA neurons were reduced by the lesions. The areas of BBB leakage were associated with increased expression of P-glycoprotein and beta 3-integrin expression suggesting, respectively, a compensatory response to inflammation and possible angiogenesis. Behavioural studies revealed that domperidone, a DA antagonist that normally does not cross the BBB, attenuated apomorphine-induced stereotypic behaviour in animals with 6OHDA lesions. This suggests that drugs which normally have no effect in brain can enter following Parkinson-like lesions. These data suggest that the events associated with DA neuron loss compromise BBB function.
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PMID:6-Hydroxydopamine-induced alterations in blood-brain barrier permeability. 1617 58

Liver tissue constructs with excretory function are crucial to developing realistic hepatocyte models for engineering effective bioartificial liver-assisted devices and for modeling the in vivo tissue. Current hepatocyte in vitro models suffer from limited or inefficient hepatocyte repolarization, which results in poor removal of xenobiotics and other waste products from the cells. We hypothesized that the temporal and spatial presentation of the cell matrix and cell-cell contacts as polarity cues would be important to define the axis of polarization to improve the excretory function of hepatocytes. The spatial presentation of polarity cues can be best achieved with sandwich configuration. We improve the temporal presentation of polarity cues by introducing the collagen overlay immediately in synchrony with cell-cell contacts instead of after 24 h in conventional sandwich culture. We demonstrate that the immediate presentation of the collagen matrix overlay enhances the formation of apicobasolateral domains, tight junctions, and the recovery of the functional activity of 2 canalicular transporters, the multidrug resistance-associated protein (Mrp2) and P-glycoprotein (P-gp) at 48 h of culture, and enhances the albumin secretion, urea production, and 7-ethoxyresorufin-O-deethylation cytochrome P450 activities of hepatocytes over 14 days of culture as compared to the 24-h overlay controls. The improvement in the excretory function of hepatocytes for the removal of waste products deleterious to cells may improve the functional maintenance and the in vivo fidelity of tissue-engineered liver constructs.
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PMID:Improved hepatocyte excretory function by immediate presentation of polarity cues. 1696 59

Peripheral inflammation can aggravate local brain inflammation and neuronal death. The blood-brain barrier (BBB) is a key player in the event. On a relevant in vitro model of primary rat brain endothelial cells co-cultured with primary rat astroglia cells lipopolysaccharide (LPS)-induced changes in several BBB functions have been investigated. LPS-treatment resulted in a dose- and time-dependent decrease in the integrity of endothelial monolayers: transendothelial electrical resistance dropped, while flux of permeability markers fluorescein and albumin significantly increased. Immunostaining for junctional proteins ZO-1, claudin-5 and beta-catenin was significantly weaker in LPS-treated endothelial cells than in control monolayers. LPS also reduced the intensity and changed the pattern of ZO-1 immunostaining in freshly isolated rat brain microvessels. The activity of P-glycoprotein, an important efflux pump at the BBB, was also inhibited by LPS. At the same time production of reactive oxygen species and nitric oxide was increased in brain endothelial cells treated with LPS. Pentosan polysulfate, a polyanionic polysaccharide could reduce the deleterious effects of LPS on BBB permeability, and P-glycoprotein activity. LPS-stimulated increase in the production of reactive oxygen species and nitric oxide was also decreased by pentosan treatment. The protective effect of pentosan for brain endothelium can be of therapeutical significance in bacterial infections affecting the BBB.
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PMID:Pentosan polysulfate protects brain endothelial cells against bacterial lipopolysaccharide-induced damages. 1699 27

Colchicine is used chiefly in the treatment of gout but is also valuable in other inflammatory diseases such as familial Mediterranean fever (FMF). Three proteins play pivotal roles in colchicine pharmacokinetics: the colchicine receptor, tubulin, which governs the plasma elimination half-life of the drug; intestinal and hepatic CYP3A4, which is key to the biotransformation of colchicine; and P-glycoprotein, a cell efflux pump that regulates the tissue distribution of colchicine, as well as its excretion via the biliary tract and kidneys. Pharmacokinetic studies have been performed using a radioimmunology assay to measure blood colchicine levels. Absorption after oral ingestion varies widely (from 24% to 88% of the dose), the volume of distribution is extremely large (7 l/kg), and binding to albumin is moderate. Colchicine is excreted chiefly through the liver and has an elimination half-life of 20-40 hours. With repeated doses of about 1mg/day, the steady-state is achieved within 8 days and concentrations range from 0.3 to 2.5 ng/ml. Studies of associations between pharmacokinetic parameters and pharmacodynamics show that effects are correlated, not to plasma levels, but to levels in leukocytes. Adverse events are not uncommon, most notably when colchicine is used in combination with drugs that interact with CYP3A4 and/or P-glycoprotein, thereby decreasing the renal and/or hepatic elimination of colchicine. Careful monitoring in this situation is effective in preventing the development of toxicity.
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PMID:Colchicine today. 1706 38

Temporal changes in physiological spaces, protein expression of transporters and enzymes, and enalapril removal were appraised in the metastatic liver tumor model developed from male Wag/Rij rats after the intraportal injection of CC531 colon adenocarcinoma cells; sham-operated preparations received PBS. Liver tissue spaces, investigated with multiple indicator dilution technique in liver perfusion studies, were unchanged at week 3 after tumor induction. At week 4, however, the sinusoidal blood volume and albumin Disse space in tumor-bearing livers were slightly lower compared with those of shams. Increased levels of the canalicular ATP transporters, P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) at week 2 (P < 0.05), unchanged levels of Ntcp, Oatp1a1, Oatp1a4, and Mct2, but decreased levels of cytochrome P450 3a2 (Cyp3a2) and glutathione S-transferase (Gst4-4) at week 4 (P < 0.05) were observed in peritumor vs. sham-operated liver tissues with Western blotting. The steady-state extraction ratio of enalapril, a substrate that enters the liver rapidly via Oatp1a1 and primarily undergoes metabolism by the carboxylesterases, was unaffected by liver metastasis at week 4 regardless of its delivery via the portal vein or hepatic artery into the perfused liver preparations.
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PMID:Transporters, enzymes, and enalapril removal in a rat (CC531-induced) liver metastatic model. 1785 65

Hypoxia and post-hypoxic reoxygenation induces disruption of the blood-brain barrier (BBB). Alterations of the BBB function after hypoxia/reoxygenation (H/R) injury remain unclear. Cyclosporin A (CsA), a potent immunosuppressant, induces neurotoxic effects by entering the brain, although the transport of CsA across the BBB is restricted by P-glycoprotein (P-gp), a multidrug efflux pump, and tight junctions of the brain capillary endothelial cells. The aim of this study was to evaluate whether the BBB after H/R damage is vulnerable to CsA-induced BBB dysfunction. We attempted to establish a pathophysiological BBB model with immortalized mouse brain capillary endothelial (MBEC4) cells. The effects of CsA on permeability and P-gp activity of the MBEC4 cells were then examined. Exposure to hypoxia for 4 h and reoxygenation for 1 h (H/R (4 h/1 h)) produced a significant decrease in P-gp function of MBEC4 cells, without changing cell viability and permeability for sodium fluorescein and Evan's blue-albumin at 7 days after H/R (4 h/1 h). CsA-induced hyperpermeability and P-gp dysfunction in MBEC4 monolayers at 7 days after H/R (4 h/1 h) were exacerbated. The possibility that CsA penetrates the BBB with incomplete functions in the vicinity of cerebral infarcts to induce neurotoxicity has to be considered.
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PMID:Adverse effect of cyclosporin A on barrier functions of cerebral microvascular endothelial cells after hypoxia-reoxygenation damage in vitro. 1793 7

Adverse drug reactions (ADRs) associated with antifungal therapy are major problems in patients with invasive fungal infections. Whether by clinical history or patterns of genetic variation, the identification of patients at risk for ADRs should result in improved outcomes while minimizing deleterious side effects. A major contributing factor to ADRs with antifungal agents relates to drug distribution, metabolism and excretion. Genetic variation in key genes can alter the structure and expression of genes and gene products (e.g., proteins). Thus far, the effort has focused on identifying polymorphisms with either empirical or predicted in silico functional consequences; the best candidate genes encode phase I and II drug-metabolizing enzymes (e.g., CYP2C19 and N-acetyltransferase), plasma proteins (albumin and lipoproteins) and drug transporters (P-glycoprotein and multidrug resistance proteins), which can affect the disposition of antifungal agents, eventually leading to dose-dependent (type A) toxicity. Less is known regarding the key genes that interact with antifungal agents, resulting in idiosyncratic (type B) ADRs. The possible role of certain gene products and genetic polymorphisms in the toxicities of antifungal agents are discussed in this review. The preliminary data address the following: low-density lipoproteins and cholesteryl ester transfer protein in amphotericin B renal toxicity; toll-like receptor 1 and 2 in amphotericin B infusion-related ADRs; phosphodiesterase 6 in voriconazole visual adverse events; flavin-containing monooxygenase, glutathione transferases and multidrug resistance proteins 1 and 2 in ketoconazole and terbinafine hepatotoxicity; CYP enzymes and P-glycoprotein in drug interactions between azoles and coadministered medications; multidrug resistance proteins 8 and 9 on 5-flucytosine bone marrow toxicity; and mast cell activation in caspofungin histamine release. This will focus on high-priority candidate genes, which could provide a starting point for molecular studies to elucidate the potential mechanisms for understanding toxicity associated with antifungal drugs as well as identifying candidate genes for large population prospective genetic association studies.
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PMID:Defining targets for investigating the pharmacogenomics of adverse drug reactions to antifungal agents. 1846 3

Cell transplantation is a potential therapy for acquired or inherited liver diseases. Donor-derived hepatocytes (DDH) have been found in humans and mice after bone marrow transplantation (BMT) but with highly variable frequencies in different disease models. To test the effect of liver repopulation after BMT in inherited cholestatic liver diseases, spgp (sister of P-glycoprotein, or bile salt export pump, abcb11) knockout mice, a model for human progressive intrahepatic cholestasis type 2 with defects in excreting bile salts across the hepatocyte canalicular membrane, were transplanted with bone marrow cells from enhanced green fluorescent protein (EGFP) transgenic donor mice after lethal irradiation. One to 6 months later, scattered EGFP-positive DDHs with positive spgp staining were observed in the liver. These hepatocytes had been incorporated into hepatic plates and stained positively with hepatocyte-specific marker albumin. RT-PCR for the spgp gene revealed positive expression in the liver of sgsp knockout mice that had received the transplant. Bile acid analysis of bile samples showed that these mice also had higher levels of total biliary bile acid and taurocholic acid concentration than knockout mice without transplantation, indicating that BMT partially improved biliary bile acid secretion. Our results indicate that bone marrow cells could serve as a potential source for restoration of hepatic functions in chronic metabolic liver disease.
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PMID:Bone marrow transplantation results in donor-derived hepatocytes in an animal model of inherited cholestatic liver disease. 1850 47

The application of taxane chemotherapy to the treatment of early-stage and advanced breast cancer has resulted in significant improvements in disease-free and overall survival. As a consequence of these improvements in disease outcome, oncologists must face the new challenge of developing additional therapies that are effective against taxane-resistant disease and are associated with a favorable toxicity profile. This article discusses some of the chemotherapeutic options available for the treatment of patients with taxane-resistant metastatic breast cancer. Newer formulations of traditional microtubule-stabilizing agents, such as albumin-bound paclitaxel, which uses a more favorable vehicle for administration compared with conventional paclitaxel, have demonstrated efficacy in this setting. Several novel microtubule-targeting agents have been shown to be less susceptible to traditional mechanisms of taxane resistance, such as the multidrug resistance phenotype associated with increased activity of the P-glycoprotein drug efflux system and the development of structural changes in tubulin. Examples of these therapies include the vinca alkaloids, such as vinorelbine and vinflunine; epothilones; and eribulin. Traditional antimetabolites, such as gemcitabine and capecitabine, used as monotherapy or combination chemotherapy have also shown efficacy in the treatment of patients with taxane-resistant breast cancer. A greater understanding of the mechanism of drug resistance, as it pertains to taxanes, will enable further development and the effective application of chemotherapeutic agents that will circumvent drug resistance and result in improvement in breast cancer control.
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PMID:Options for the treatment of patients with taxane-refractory metastatic breast cancer. 1863 1

Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) developed for the treatment of HIV-1 infection. It has a high genetic barrier to the emergence of viral resistance, and maintains its antiviral activity in the presence of common NNRTI mutations. The pharmacokinetics of etravirine in HIV-infected patients at the recommended dosage of 200 mg twice daily demonstrates moderate intersubject variability and no time dependency. Due to substantially lower exposures when taken on an empty stomach, etravirine should be administered following a meal. The drug is highly protein bound (99.9%) to albumin and alpha(1)-acid glycoprotein and shows a relatively long elimination half-life of 30-40 hours. Etravirine is metabolized by cytochrome P450 (CYP) 3A, 2C9 and 2C19; the metabolites are subsequently glucuronidated by uridine diphosphate glucuronosyltransferase. Renal elimination of etravirine is negligible. Etravirine has the potential for interactions by inducing CYP3A and inhibiting CYP2C9 and 2C19; it is a mild inhibitor of P-glycoprotein but not a substrate. The drug interaction profile of etravirine has been well characterized and is manageable. No dosage adjustments are needed in patients with renal impairment or mild to moderate hepatic impairment. Race, sex, bodyweight and age do not affect the pharmacokinetics of etravirine. In the two phase III trials DUET-1 and DUET-2, no relationship was demonstrated between the pharmacokinetics of etravirine and the primary efficacy endpoint of viral load below 50 copies/mL or the safety profile of etravirine.
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PMID:Clinical pharmacokinetics and pharmacodynamics of etravirine. 1972 91


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