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)

The multidrug-resistance P-glycoprotein (Pgp) was initially identified as an energy-dependent proton pump, which transports a variety of non-related compounds out of chemotherapy-resistant cancer cells. Molecular biological investigations using knockout mice for the mouse homologue of the human Pgp showed that these mice partially lack a functioning blood-brain barrier, indicating that Pgp has an important role in the blood-brain barrier as its normal function. The presence of Pgp expression in formalin-fixed and wax-processed tissue sections can be assessed using the monoclonal antibody, JSB-1. Since no data on the developmental expression of Pgp are available, we stained a developmental series of human brain sections with JSB-1. Our results indicate that Pgp expression in endothelia of brain microvessels occurs regularly in embryos of about 30-mm crown-rump length (CRL). Strong reactivity is seen in blood vessels of fetuses from 123-mm CRL. There is also reactivity in pial blood vessels but not in choroid plexus blood vessels known to be without a blood-brain barrier. Pgp expression is therefore an early marker of the blood-brain barrier in the developing human brain.
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PMID:The multidrug-resistance P-glycoprotein (Pgp, MDR1) is an early marker of blood-brain barrier development in the microvessels of the developing human brain. 927 37

Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models. Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin. CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance. In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.
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PMID:Clinical pharmacokinetics of fluvastatin. 1136 92

Proton pump inhibitors are a class of drugs which are widely prescribed for acid-related diseases. They are primarily metabolized by CYP2C19 and CYP3A4. It is unknown so far whether proton pump inhibitors are also substrates of the ATP-dependent efflux transporter P-glycoprotein. Moreover, it is not established whether proton pump inhibitors are also inhibitors of P-glycoprotein function. The aim of our study was therefore to characterize omeprazole, lansoprazole and pantoprazole as P-glycoprotein substrates and inhibitors. Polarized transport of these compounds was assessed in P-glycoprotein-expressing Caco-2 and L-MDR1 cells. Inhibition of P-glycoprotein-mediated transport was determined using the cyclosporine analogue PSC-833 (valspodar) as P-glycoprotein inhibitor. Inhibition of efflux transport by omeprazole, lansoprazole and pantoprazole was assessed using digoxin as P-glycoprotein substrate. At concentrations of 5 microM, basal-to-apical transport of omeprazole, lansoprazole and pantoprazole was greater than apical-to-basal transport in Caco-2 and L-MDRI cells. Addition of PSC-833 (1 microM) showed a clear effect only for lansoprazole, suggesting that other transporters contribute to omeprazole and pantoprazole cellular translocation. Furthermore, all of the tested compounds inhibited digoxin transport with IC50 values of 17.7, 17.9 and 62.8 microM for omeprazole, pantoprazole and lansoprazole, respectively. In summary, our data provide evidence that proton pump inhibitors are substrates and inhibitors of P-glycoprotein. These findings might explain some of the drug interactions with proton pump inhibitors observed in vivo.
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PMID:Interaction of omeprazole, lansoprazole and pantoprazole with P-glycoprotein. 1177 10

Studies of the multidrug-resistance protein 1 (MRP1) have been hampered by the lack of a simple expression system allowing for rapid generation of mutants and yielding milligram amounts of protein. Here, we describe a Saccharomyces cerevisiae expression system that meets those conditions. MRP1 was expressed under the control of the constitutive PMA1 (yeast proton pump) promoter. The best conditions for expression were determined, including the use of the chemical chaperone glycerol, which increased MRP1 expression. N-terminal poly-histidine or FLAG affinity tags reduce MRP1 expression, whereas the same tags fused to the C-terminus had no effect. All the fusion proteins were functional. We conclude that because of its low cost and simplicity, the S. cerevisiae-based MRP1-expression system will be useful for studies where a large number of mutants or milligram amounts of purified MRP1 are needed.
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PMID:Expression of functional multidrug-resistance protein 1 in Saccharomyces cerevisiae: effects of N- and C-terminal affinity tags. 1281 67

An in vitro study has recently suggested that a proton pump inhibitor, omeprazole, is a modest substrate of P-glycoprotein. Several studies have shown P-glycoprotein is involved in the absorption and excretion of fexofenadine. Therefore, we examined the effect of fexofenadine on the pharmacokinetics of omeprazole. Eight healthy volunteers participated in this study. They received a single oral dose of 40 mg omeprazole before and after 60 mg fexofenadine (10 doses over 6 days). Blood samplings were performed up to 8 hr after each dosing. Plasma concentrations of omeprazole and its two metabolites were quantified with high-performance liquid chromatography. In addition, the effect of fexofenadine on P-glycoprotein function was examined by flow cytometry using rhodamine 123 and CD56-positive lymphocytes. Comparison of the pharmacokinetic parameters of omeprazole before and after fexofenadine revealed that there were no differences in peak concentration, time to peak concentration, area under the time concentration curve up to 8 hr, and elimination half-life. There were also no differences in these pharmacokinetic parameters for the two metabolites of omeprazole. Flow cytometric analysis revealed that fexofenadine did not inhibit the efflux of rhodamine 123. This study indicated that there was probably no drug interaction between omeprazole and fexofenadine, which might be due to less contribution of P-glycoprotein to omeprazole absorption, insufficient inhibitory effect of fexofenadine on P-glycoprotein, or the involvement of other transporters such as organic anion transporting polypeptides.
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PMID:Fexofenadine does not affect omeprazole pharmacokinetics: both are putative P-glycoprotein substrates. 1512 96

A proton pump inhibitor (PPI) plus two antibiotics (amoxicillin and either clarithromycin or metronidazole) are recommended for treatment of acid-related disorders with Helicobacter pylori (H. pylori) infection. The aim of this pharmacogenetic study was to evaluate the efficacy of triple therapy with PPIs on eradication of H. pylori infection in relation to cytochrome P450 2C19 (CYP2C19) and P-glycoprotein (MDR1) gene polymorphisms. The retrospective study involved 70 Polish Caucasian patients with H. pylori infection, diagnosed and treated with one of the two different triple therapy regimens [omeprazole, amoxicillin, and clarithromycin (OAC) or pantoprazole, amoxicillin, and metronidazole (PAM)]. Using genomic DNA, CYP2C19 (*2 and *3) and C3435T MDR1 alleles were determined by means of polymerase chain reaction-restriction fragment length polymorphism assays. A significantly higher prevalence (P<0.05) of heterozygous extensive metabolizers (hetEM) with CYP2C19*1/*2 genotype (32.4% versus 8.3%) and homozygous with 3435TT MDR1 genotype (38.2% versus 13.9%) was found in patients cured after the first cycle of triple therapy than in patients with failure of eradication after the first cycle. CYP2C19*1/*2 and 3435TT MDR1 genotypes as well as PAM regimen of treatment were also predictive of successful eradication of H. pylori infection after the first cycle of triple therapy at univariate/multivariate logistic regression analysis. This pharmacogenetic study on the influence of different CYP2C19 and C3435T MDR1 genotypes on H. pylori eradication suggests that CYP2C19 and MDR1 polymorphisms may be independent predictable determinants of the efficacy of triple therapy including PPI. The PAM regimen of treatment seems to be more effective after the first cycle of the therapy than the OAC regimen.
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PMID:Effect of CYP2C19 and MDR1 polymorphisms on cure rate in patients with acid-related disorders with Helicobacter pylori infection. 1597 89

Proton pump inhibitors are used extensively for the treatment of gastric acid-related disorders because they produce a greater degree and longer duration of gastric acid suppression and, thus, better healing rates, than histamine H(2) receptor antagonists. The need for long-term treatment of these disorders raises the potential for clinically significant drug interactions in patients receiving proton pump inhibitors and other medications. Therefore, it is important to understand the mechanisms for drug interactions in this setting. Proton pump inhibitors can modify the intragastric release of other drugs from their dosage forms by elevating pH (e.g. reducing the antifungal activity of ketoconazole). Proton pump inhibitors also influence drug absorption and metabolism by interacting with adenosine triphosphate-dependent P-glycoprotein (e.g. inhibiting digoxin efflux) or with the cytochrome P450 (CYP) enzyme system (e.g. decreasing simvastatin metabolism), thereby affecting both intestinal first-pass metabolism and hepatic clearance. Although interactions based on the change of gastric pH are a group-specific effect and thus may occur with all proton pump inhibitors, individual proton pump inhibitors differ in their propensities to interact with other drugs and the extent to which their interaction profiles have been defined. The interaction profiles of omeprazole and pantoprazole have been studied most extensively. A number of studies have shown that omeprazole carries a considerable potential for drug interactions, since it has a high affinity for CYP2C19 and a somewhat lower affinity for CYP3A4. In contrast, pantoprazole appears to have lower potential for interactions with other medications. Although the interaction profiles of esomeprazole, lansoprazole and rabeprazole have been less extensively investigated, evidence suggests that lansoprazole and rabeprazole seem to have a weaker potential for interactions than omeprazole. Although only a few drug interactions involving proton pump inhibitors have been shown to be of clinical significance, the potential for drug interactions should be taken into account when choosing a therapy for gastric acid-related disorders, especially for elderly patients in whom polypharmacy is common, or in those receiving a concomitant medication with a narrow therapeutic index.
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PMID:Pharmacokinetic drug interaction profiles of proton pump inhibitors. 1694 63

Medications to address gastrointestinal disorders are among the most commonly dispensed somatic medications. The authors examine proton pump inhibitors, H(2) blockers, 5-HT(3) receptor-antagonists, and a few other drugs that are used to address this domain of medical concerns. The metabolic pathways, interactions with the P-glycoprotein transporter, and capabilities of inhibiting or inducing metabolic enzymes are elucidated for each drug. Specific drug-drug interactions with each agent are also detailed, including both psychotropic and non-psychotropic agents. Also, the article explores how different genotypic variants for specific cytochrome P450 enzymes have an impact on the effectiveness and likelihood of drug-drug interactions relating to specific gastro-intestinal medications.
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PMID:Gastrointestinal medications. 1720 56

St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and mechanistic studies are warranted to explore the interaction of SJW with other important drugs and the potential clinical impact.
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PMID:Clinical drugs that interact with St. John's wort and implication in drug development. 1867 95

P-glycoprotein is important in local antibiotic resistance. Aim was to evaluate the role of P-glycoprotein in local antibiotic resistance in patients with antral gastritis during antibiotic therapy to Helicobacter pylori infection. In the group of 53 patients with pathohistologically verified gastritis and microbiologically confirmed H. pylori infection (no signs of antimicrobial resistance) we have determined P-glycoprotein activity in gastric mucosa biopsy specimens, and compared them with the P-glycoprotein activity in 12 control subjects with normal endoscopic findings. The H. pylori positive patients were treated according to Maastricht protocol with short-term 7-day therapy consisting of two antibiotics (amoxicillin and azithromycin/metronidazole and clarithromycin) and a proton pump inhibitor P-glycoprotein activity was determined in rhodamine dye efflux test and quantified by ratio of the mean fluorescence (RMF) in flow cytometry analysis. H. pylori was successfully eradicated in the first cycle in 20 patients, whereas therapy was continued in 33 patients. The mean pre-treatment RMF values were higher in patients with H. pylori infection then in control subjects (p < 0.0046). RMF was also higher in patients with multiple therapeutic failure than in those with successful H. pylori eradication (p < 0.0001). RMF increased significantly during the antibiotic therapy (p < 0.05). P-glycoprotein might be one of the causes of therapy failure in patients with H. pylori. Our study confirms the importance of quantitative evaluation of P-glycoprotein expression during antibiotic treatment response.
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PMID:The importance of P-glycoprotein multidrug transporter activity measurement in patients with Helicobacter pylori infection. 2010 60


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