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  • 1
    Electronic Resource
    Electronic Resource
    Cellular localization and functional expression of P-glycoprotein in rat astrocyte cultures (2004)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 89 (2004), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: We investigated the cellular/subcellular localization and functional expression of P-glycoprotein, an ATP-dependent membrane-associated efflux transporter, in astrocytes, a brain parenchyma compartment that is poorly characterized for the expression of membrane drug transporters. Analyses were carried out on primary cultures of astrocytes isolated from the cerebral cortex of neonatal Wistar rats and CTX TNA2, an immortalized rat astrocyte cell line. Both cell cultures display morphological features typical of type I astrocytes. RT-PCR analysis revealed mdr1a and mdr1b mRNA in primary cultures of astrocytes and in CTX TNA2 cells. Western blot analysis using the P-glycoprotein monoclonal C219 antibody detected a single band of appropriate size in both cell systems. Immunocytochemical analysis using the monoclonal antibodies C219 and MRK16 labeled P-glycoprotein along the plasma membrane, caveolae, coated vesicles and nuclear envelope. Immunoprecipitation studies using the caveolin-1 polyclonal H-97 antibody demonstrated that P-glycoprotein is physically associated with caveolin-1 in both cell culture systems. The accumulation of [3H]digoxin (an established P-glycoprotein substrate) by the astrocyte cultures was significantly enhanced in the presence of standard P-glycoprotein inhibitors and an ATP depleting agent. These results demonstrate the cellular/subcellular location and functional expression of P-glycoprotein in rat astrocytes and suggest that this glial compartment may play an important role in the regulation of drug transport in the CNS.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.2004.02417.x
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  • 2
    Electronic Resource
    Electronic Resource
    Comparison of the accumulation and efflux kinetics of technetium-99m sestamibi and technetium-99m tetrofosmin in an MRP-expressing tumour cell line (2000)
    Springer
    European journal of nuclear medicine 27 (2000), S. 1786-1792 
    Details
    ISSN: 1619-7089
    Keywords: Technetium-99m sestamibi Technetium-99m tetrofosmin Multidrug resistance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The potential clinical use of technetium-99m labeled sestamibi (Tc-MIBI) and tetrofosmin (Tc-Tfos) to image tumours is currently being evaluated. In this study, the accumulation and efflux of Tc-MIBI and Tc-Tfos in the nasopharyngeal carcinoma cell line CNE-1 were examined in the presence or absence of various inhibitors of P-glycoprotein (PGP) and/or multidrug resistance associated protein (MRP) activity [GG918, PSC833, verapamil (Vrp), cyclosporin A (CsA) and buthionine sulfoximine (BSO)]. Reverse-transcriptase polymerase chain reaction analysis and immunodetection of the CNE-1 cells detected expression of MRP, MRP1 and MRP2 but not PGP. Tc-MIBI and Tc-Tfos accumulation was increased (P〈0.0001) and efflux decreased (P〈0.05) in the presence of BSO, CsA, Vrp and PSC833 but not GG918, which is a specific inhibitor of PGP. The absolute accumulation of Tc-MIBI was approximately twofold higher than that seen with Tc-Tfos, whereas the addition of inhibitors caused a much greater suppression of Tc-Tfos transport (〉2 times greater than for Tc-MIBI). However, no qualitative differences in inhibitors were seen between Tc-MIBI and Tc-Tfos. These results suggest that both Tc-MIBI and Tc-Tfos are substrates for the MRP transporter and that PSC833, Vrp, CsA and BSO but not GG918 can inhibit MRP activity. These results indicate that Tc-MIBI and Tc-Tfos may be suitable imaging agents for detecting MRP-mediated drug resistance in human cancers.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002590000375
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  • 3
    Electronic Resource
    Electronic Resource
    Selective Effect of Adjuvant Arthritis on the Disposition of Propranolol Enantiomers in Rats Detected Using a Stereospecific HPLC Assay (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 294-299 
    Details
    ISSN: 1573-904X
    Keywords: propranolol ; inflammation ; stereoselective ; adjuvant arthritis ; enantiomer ; HPLC ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Nonstereospecific studies have indicated that the pharmacokinetics of propranolol (PR) are altered in inflammatory conditions such as arthritis. However, as the kinetics and dynamics of PR are stereoselective, we examined the effect of adjuvant arthritis (AA) on the disposition of the individual enantiomers. A novel normal-phase stereospecific HPLC assay for PR was developed involving chiral derivatization with S-(naphthyl)ethyl isocyanate and fluorescence detection. Oral and iv doses of racemic PR were administered to control and AA rats (n = 6). AA had no significant effect on either clearance or S:R ratio after iv doses. On the other hand, after oral doses, clearance was significantly decreased in AA. Although significant for both enantiomers, this effect was more pronounced on the less active R-enantiomer. The AUC R:S ratio was, therefore, significantly altered (AA, 14 ± 3.0; control, 4.3 ± 1.2). Increased total (S + R) plasma concentrations of PR in AA, possibly due to a reduced intrinsic clearance, therefore, reflect mainly increased concentrations of the less active R-enantiomer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018907431893
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  • 4
    Electronic Resource
    Electronic Resource
    Characterization of Guanidine Transport in Human Renal Brush Border Membranes (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 936-941 
    Details
    ISSN: 1573-904X
    Keywords: brush-border membrane vesicles ; organic cation transport ; tetraethylammonium ; guanidine ; human kidney ; transporters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Organic cation transporters in the renal proximal tubule are important in the secretion of many clinically used drugs and their metabolites. The goal of this study was to determine the mechanisms of guanidine transport in human kidney. Methods. Brush-border membrane vesicles were prepared from donor human kidneys deemed unsuitable for renal transplantation. Results. Uptake of [14C]-guanidine (50 μM) in the vesicles, as determined by rapid filtration, was significantly greater in the presence of an outwardly-directed proton gradient, at all early time points, than in the absence of the gradient. Proton-stimulated uptake of [14C]-guanidine at 30 sec (32.0 ± 1.24 pmol/mg protein) was significantly inhibited by a number of organic cations including 5 mM unlabeled guanidine (14.8 ± 1.84 pmol/mg protein) and 5 mM MIBA (9.14 ± 3.80 pmol/ mg protein), but not by 5 mM TEA (28.4 ± 5.67 pmol/mg protein). Guanidine, but not TEA, trans-stimulated [14C]-guanidine uptake. Conversely, TEA, but not guanidine, trans-stimulated [14C]-TEA uptake in the vesicles. The proton-dependent transport of guanidine was characterized by a Km of 3.52 ± 0.42 mM (SE) and a Vmax of 34.6 ± 8.64 pmol/mg protein/sec (SE). Conclusions. These results demonstrate that guanidine transport in human renal brush border membrane vesicles is stimulated by a proton gradient. Evidence was obtained suggesting that the transporter for guanidine is distinct from the previously described organic cation proton antiporter for TEA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012164203648
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  • 5
    Electronic Resource
    Electronic Resource
    Functional and Molecular Characteristics of Na+-dependent Nucleoside Transporters (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1524-1532 
    Details
    ISSN: 1573-904X
    Keywords: nucleoside transporters ; review ; nucleoside analogs ; expression systems ; adenosine ; intestinal absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Nucleoside transporters play a critical role in the absorption, disposition, and targeting of therapeutically used nucleosides and nucleoside analogs. This review is focused on the Na+-dependent, concentrative nucleoside transporters which are found in a variety of cells including renal, intestinal and hepatic epithelia. Five major Na+-dependent nucleoside transporter subtypes have been characterized in isolated tissue preparations: Nl is purine selective; N2 is pyrimidine selective and N3−N5 exhibit variable selectivity for both purine and pyrimidine nucleosides. The recent cloning of Nl and N2 nucleoside transporters has provided the first information on the molecular function and structure of concentrative nucleoside transporters. In this manuscript we review the characteristics of the various subtypes of nucleoside transporters and the molecular structure, functional properties, and tissue distribution of the cloned Na+-dependent nucleoside transporters. In addition, the interactions of nucleosides and nucleoside analogs with the cloned transporters in mammalian and amphibian expression systems are presented. Mammalian expression systems may be particularly useful during drug development in screening potential compounds for improved bioavailability and tissue specific targeting. Finally, we present our view of future areas of study in the field of nucleoside transporters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012113931332
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  • 6
    Electronic Resource
    Electronic Resource
    Decreased Expression and Activity of P-GIycoprotein in Rat Liver During Acute Inflammation (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 706-711 
    Details
    ISSN: 1573-904X
    Keywords: multidrug resistance ; P-glycoprotein ; inflammation ; acute phase response ; gene regulation ; drug disposition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Drug disposition is often altered in inflammatory disease. Although the influence of inflammation on hepatic drug metabolism and protein binding has been well studied, its impact on drug transport has largely been overlooked. The multidrug resistance (MDR) gene product, P-glycoprotein (P-gp) is involved in the active secretion of a large variety of drugs. Our goal was to ascertain the influence of acute inflammation (AI) on the expression and functional activity of P-gp. Methods. AI was induced in rats through turpentine or lipopolysaccharide (LPS) administration. Expression of P-gp in liver was detected at the level of protein on Western blots using the monoclonal antibody C-219 and at the level of mRNA using an RNase protection assay. P-gp mediated transport activity was assessed by measuring the verapamil-inhibitable efflux of rhodamine 123 (R123) in freshly isolated hepatocytes. Results. Turpentine-induced AI significantly decreased the hepatic protein expression of P-gp isoforms by 50−70% and caused a significant 45−65% reduction in the P-gp mediated efflux of R123. Diminished mRNA levels of all three MDR isoforms were seen. LPS-induced AI similarly resulted in significantly reduced levels and activity of P-gp in liver. Although differences in the constitutive levels of P-gp were seen between male and female rats, the influence of AI on P-gp expression and activity was not gender specific. Conclusions. Experimentally-induced inflammation decreases the in vivo expression and activity of P-gp in liver. This is the first evidence that expression of P-gp is modulated in response to experimentally-induced inflammation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011962818051
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