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)

Cefoperazone is a third generation cephalosporin antibiotic with a broad spectrum against gram-positive and gram-negative bacteria. It is clinically effective in the treatment of the biliary tract infections. In the present study, we utilized microdialysis sampling technique with shunt linear probe for continuous monitoring levels of cefoperazone from rat biliary ducts. The effects of berberine (a potential P-glycoprotein enhancer) pretreatment were also evaluated. Analysis of cefoperazone in the dialysates was achieved using a reversed phase RP-18 column (250 mm x 4.6 mm i.d.; particle size 5 microm) maintained at ambient temperature. The mobile phase comprised 100 mM monosodium phosphate (pH 5.5)-methanol (70:30, v/v), and the flow rate of the mobile phase was 1 ml/min. The UV detector wavelength was set at 254 nm. The area under the concentration-time curve and elimination half-life of cefoperazone were about 242.3+/-13.4 min mg/ml and 64.1+/-28.2 min, respectively. No significant effect was showed on the pharmacokinetics of cefoperazone with berberine pretreatment. This study represents a successful application of biliary microdialysis sampling technique, which is feasible for pharmacokinetic and biliary drug excretion studies.
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PMID:Quantitative determination of unbound cefoperazone in rat bile using microdialysis and liquid chromatography. 1756 Jul 51

Oseltamivir is an ethyl ester prodrug of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), the anti-influenza drug. Abnormal behavior has been suspected to be associated with oseltamivir medication in Japan. The purpose of the present study is to examine the involvement of transporters in the brain distribution of oseltamivir and its active form Ro 64-0802 across the blood-brain barrier (BBB). The brain-to-plasma concentration ratio (K(p,brain)) of oseltamivir after i.v. infusion of oseltamivir in FVB mice was increased by pretreatment with 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), a dual inhibitor for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), whereas that of Ro 64-0802 was only slightly increased. Furthermore, the distribution volume of Ro 64-0802 following i.v. administration of Ro 64-0802 in the brain was similar to the capillary volume, suggesting its minimal distribution. The K(p,brain) value of oseltamivir in multidrug-resistant (Mdr) 1a/1b P-gp knockout mice was 5.5-fold higher than that in wild-type mice and comparable with that obtained by pretreatment with GF120918, whereas it was unchanged in Bcrp knockout mice. The K(p,brain) value of oseltamivir was significantly higher in newborn rats, which is in good agreement with the ontogenetic expression profile of P-gp. Intracellular accumulation of oseltamivir was lower in human and mouse P-gp-expressing cells, which was reversed by P-gp inhibitor valspodar (PSC833). These results suggest that P-gp limits the brain uptake of oseltamivir at the BBB and that Ro 64-0802 itself barely crosses the BBB. However, it may be possible that Ro 64-0802 is formed in the brain from the oseltamivir, considering the presence of carboxylesterase in the brain endothelial cells.
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PMID:P-glycoprotein restricts the penetration of oseltamivir across the blood-brain barrier. 1803 6

The objective of this study was to examine the effect of ion-pair complexation with endogenous bile salts on the transport of a quarternary ammonium organic cationic (OC) drug, berberine, across the Caco-2 and LLC-PK1 cell monolayers. The basolateral-to-apical (BL-AP) transport of berberine in Caco-2 cells was temperature dependent and 10-fold higher than that of the apical-to-basolateral (AP-BL) transport. Similar results were observed for the transport of berberine across the LLC-PK1 cells. Moreover, the BL-AP transport in the Caco-2 cells was significantly reduced by the cis-presence of P-glycoprotein (P-gp) inhibitors such as cyclosporine A, verapamil, and digoxin. These results suggest that an efflux transporter, probably P-gp, is involved in the Caco-2 cell transport. The Km and Vmax values for the carrier-mediated transport were estimated to be 83.4 mM and 7640 pmole/h/cm2, respectively. The apparent partition coefficient (APC) of berberine between n-octanol and a phosphate buffer (pH 7.4) was increased by the presence of an organic anion (OA), taurodeoxycholate (TDC, a bile salt), suggesting the formation of a lipophilic ion-pair complex between an OC (berberine) and an OA (TDC). Despite the ion-pair complexation, however, the BL-AP transport of berberine across the Caco-2 and LLC-PK1 cells was not altered by the cis-presence of bile salts or the rat bile juice. This is consistent with the reportedly unaltered secretory transport of a quarternary ammonium compound, tributylmethylammonium (TBuMA), across the Caco-2 cell monolayers in the cis-presence of bile salts or the rat bile juice, but not with our previous report in which the secretory transport of TBuMA across the LLC-PK1 cell was increased in the cis-presence of TDC. Therefore, the effect of ion-pair formation with the bile components or bile salts on the secretory transport of OCs appears to depend on the molecular properties of OCs (e.g., molecular weight, lipophilicity and affinity to relevant transporters) and the characteristics of cell strains (e.g., expression and contribution of responsible transporters to the transport).
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PMID:Effect of ion-pair formation with bile salts on the in vitro cellular transport of berberine. 1827 15

An assessment of energetic costs associated with P-glycoprotein (P-gp)-mediated xenobiotic efflux is important in understanding the energy budgets, tradeoffs, and fitness of organisms inhabiting contaminated environments. Here, a functional characterization and determination of the energetic costs associated with doxorubicin (DOX) efflux was examined in isolated hepatocytes of rainbow trout. The accumulation and efflux of DOX were both concentration dependent. The efflux of DOX over a 3 h incubation period resulted in a significant decrease in intracellular ATP concentrations (maximum decrease 25%) compared to control baseline levels, while significant increases in concentrations of ADP (max. 26%), AMP (max. 36%) and inorganic phosphate (max. 11%). were observed. In addition, significant reductions in the adenylate energy charge ([AEC]: max 11%), and phosphorylation potential ([PP]: max. 53%) were shown in cells incubated with DOX compared to control cells. Inhibition of DOX efflux (max. 61%) by the non-competitive P-gp inhibitor tariquidar (XR9576), demonstrated that changes in ATP, ADP, AMP, inorganic phosphate concentrations, AEC and PP in DOX-exposed hepatocytes were mainly due to P-gp activity. Overall, these results indicate that the exposure of trout hepatocytes to DOX increases energetic and metabolic costs that are associated specifically with P-gp efflux activity.
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PMID:Functional and energetic characterization of P-gp-mediated doxorubicin transport in rainbow trout (Oncorhynchus mykiss) hepatocytes. 1866 92

Membrane and membrane-associated proteins are rich in known or potential pharmaceutical drug targets for carcinogenesis. In order to systemically analyze membrane proteins of human breast cancer, we isolated membrane from MCF-7 cells by sequential extraction by washing with three different buffers, namely, phosphate buffer (5 mM, pH 8.0), Tris (40 mM, pH 9.5), and sodium carbonate (100 mM pH 11). The extracted proteins were separated by two-dimensional gel electrophoresis (2-DE) using cup-loading and were then analyzed by peptide mass fingerprinting (PMF). A total of 137 spots from the gels of the three procedures were successfully identified. They corresponded to 79 distinct proteins. Among them, 22 exclusive proteins belonging to each washing procedure were also found, including P-glycoprotein, endoplasmin, Stress-70 protein, ADAM 10, protein disulfide isomerase, and glutamate receptor. These results indicate phosphate buffer to be the most beneficial for enrichment of peripheral membrane proteins, and sodium carbonate is beneficial for the presentation of integral membrane proteins but usually with poor resolution. The reference maps and identified proteins will serve as a basis for the further investigation of breast cancer, especially the proteomic comparison among different cell types of breast cancer, or among the different stages in the drug interfering process of the MCF-7 cell line.
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PMID:Membrane protein analysis of human breast cancer cell line MCF-7 by different membrane washing methods. 1870 47

The inhibitory effects of procyanidine, one of the components from the bark of Pinus massoniana Lamb, on the P-glycoprotein (P-gp) function of the blood-brain barrier (BBB) were studied using in vitro rat brain microvessel endothelial cells (RBMECs) and nude mice transplanted with human cerebroma. Quantitative accumulation and efflux of rhodamine 123 (Rh123), a P-gp substrate, were determined using a fluorescence spectrophotometer as a measure of P-gp function. Procyanidine markedly increased the accumulation of Rh123 by inhibiting its efflux in a dose-dependent manner. A 5-fold increase in cellular Rh123 was observed for procyanidine at 10 micromol/L. The verapamil-stimulated ATPase activity in plasma membrane vesicles from the RBMECs was estimated by measuring inorganic phosphate liberation. Procyanidine significantly inhibited the verapamil-induced P-gp ATPase activity by 78% when pretreated with 10 micromol/L in a concentration-dependent manner. The inhibition of P-gp by procyanidine was suggested to be at least partly due to its inhibition of P-gp ATPase. Procyanidine markedly improved the therapeutic effects of adriamycin (ADM) on nude mice transplanted with human cerebroma, compared with solitary treatment of ADM. The combination of 80 mg/kg procyanidine with 2 mg/kg ADM significantly elevated the days of survival with an increase in life span of 76%. The findings suggested that procyanidine was a potent inhibitor of P-gp on BBB and could improve the therapeutic effects on cerebral tumors of some drugs which are difficult to accumulate in the brain.
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PMID:Inhibition of P-glycoprotein function by procyanidine on blood-brain barrier. 1917 64

Flavonoids form a large class of phenolic substances widely distributed in nature and exhibit several biological effects. P-glycoprotein is part of a large family of efflux transporters found in the gut, gonads and other organs. Male albino rats were used for this study. The whole small intestine was flushed with 50 ml of ice-cold saline after sacrificing the animal with an overdose of pentobarbital. The small intestine was isolated and divided into duodenum, jejunum and ileum. Each segment was everted, a 5-cm long sac was prepared, 1 ml of nitrendipine solution was introduced into the everted sac (serosal side), and both ends of the sac were ligated tightly. The sac containing nitrendipine solution was immersed in 30 ml of Dulbecco's phosphate buffer solution (D-PBS) containing 25 mM glucose and the same concentration of different bioflavonoids, viz., diosmin, quercetin, chrysin, methyl hesperidin and gossypin, was introduced into the mucosal side. Transport of nitrendipine from serosal to mucosal surfaces across the intestine was determined by collecting samples from the mucosal medium periodically at different intervals: 0, 10, 20, 30, 60, 90 and 120 minutes. The samples were analyzed by HPLC. Diosmin and quercetin decreased the transport rate of nitrendipine to nearly the same extent in all regions. Chrysin and gossypin decreased the transport rate of nitrendipine to a greater extent in the ileum than in the duodenum and jejunum. Methyl hesperidin caused inhibition of nitrendipine transport in the ileum and jejunum, but not in the duodenum. All bioflavonoids, i.e., quercetin, diosmin, methyl hesperidin, gossypin and chrysin, decreased the transport of nitrendipine, a P-gp substrate in the rat intestine. The highest expression of P-gp was found in the ileum followed by the jejunum and duodenum.
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PMID:Influence of some bioflavonoids on the transport of nitrendipine. 1932 73

We have developed an easy and sensitive method to measure P-glycoprotein (P-gp) activity using [gamma-(32)P]ATP and charcoal. This method utilizes the nature of adsorption of organic phosphate to charcoal. The standard assay method is as follows: the reaction mixture (20 microl) of 1 mM [gamma-(32)P]ATP (1 Ci/mol), 2.5 microg P-gp membranes, and the drug was incubated for 30 min, and 50 microl of 10% charcoal suspension in 0.1 M phosphate buffer at pH7.3 was then added to the mixture. The solution was centrifuged and the supernatant (20 microl) in duplicate containing inorganic (32)P was spotted onto filter paper, and radioactivity was measured by radio-image analyzer. This method can reduce the amount of P-gp membrane compared to the conventional method utilizing coloring of the inorganic phosphate-molybdate reaction. This method is also applicable to other ATP-binding cassette (ABC) transporters in phosphate buffer.
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PMID:A new method to measure P-gp (ABCB1) activity. 1935 60

The Kampo medicines are more and more often used in recent years, usually together with the western drugs. The need for the investigation of drug interactions between Kampo medicines and western drugs are, therefore, widely recognized. Among the various possible causes for the drug-drug interactions, those related to pharmacokinetics such as drug metabolism and transport are regarded as most frequent and clinically important. In the present study, the effects of Kampo medicines on the P-glycoprotein (P-gp), one of the major drug transporters, were investigated in in vitro studies using human P-gp membranes. The P-gp activity in the presence and absence of commonly used 50 Kampo medicines was evaluated by the ATPase assay detecting the inorganic phosphate produced by the ATP hydrolysis. The ATPase activity was inhibited by most of the Kampo medicines studied, indicating the possibility of their inhibiting the P-gp. The degree of inhibition in the presence of verapamil, a P-gp substrate, showed a significant correlation with that in the absence of verapamil. Furthermore, the inhibitory effect of the Kampo medicines on the ATPase activity correlated with their licorice root (kanzo) content, suggesting the contribution of licorice root in the P-gp inhibition. Because licorice root is one of the most common ingredients in the Kampo medicines and is also often used in the food as a sweetener, it might be necessary to pay attention on the interaction between the licorice root-containing drug/food and the number of drugs transported by P-gp.
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PMID:Effects of Kampo medicines on P-glycoprotein. 1995 21

Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. Using the t(4;11) ALL line SEM, we evaluated chemotherapy resistance in NOD.CB17-Prkdcscid/J mice. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, mice were injected intraperitoneally with phosphate-buffered saline (PBS), or vincristine (0.5mg/kg body weight) three times per week for 4weeks (n=8 per group). The level of P-glycoprotein in SEM cells was increased 3-fold by vincristine treatment compared to PBS-treated mice. Survival curves showed that leukemia cell growth was initially delayed by vincristine treatment, but the mice eventually succumbed to disease. These data describe a novel inducible model for investigating multi-drug resistance mechanisms in high-risk t(4;11) ALL.
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PMID:Novel in vivo model of inducible multi-drug resistance in acute lymphoblastic leukemia with chromosomal translocation t(4;11). 2038 55


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