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  • 1
    Electronic Resource
    Electronic Resource
    Cellular and molecular mechanisms of renal tubular secretion of organic anions and cations (1998)
    Springer
    Clinical and experimental nephrology 2 (1998), S. 100-108 
    Details
    ISSN: 1437-7799
    Keywords: proximal tubules ; tubular secretion ; transporter ; organic anion ; organic cation ; xenobiotics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A wide variety of endogenous organic ions and xenobiotics are secreted into the urine via organic anion and cation transport systems, expressed in brush-border and basolateral membranes of renal tubular cells. Using membrane vesicles isolated from the kidney, cultured renal epithelial cells, isolated renal tubules, and slices of renal cortex, extensive studies have been done regarding the mechanisms of renal tubular secretion of organic ions. Basolateral entry of organic anions is mediated by the organic anion/dicarboxylate exchange system, whereas apical extrusion of organic anions from epithelial cells is mediated by an anion exchanger and/or by membrane potential-sensitive transport systems. Studies using membrane vesicles have made clear the fact that the basolateral transport of organic cations is stimulated by inside-negative membrane potential, whereas the transport of organic cations in brush-border membranes is achieved by a proton gradient. Trasport studies using cultured renal epithelial cells have shown other aspects of organic ion transport, such as regulatory mechanisms for transcellular transport of orgnaic anions and cations. The recent development of molecular techniques has greatly advanced our understanding of the molecular aspects of various transport processes. In 1994, a cDNA clone encoding the prototype organic cation transporter was isolated from rat kidney. Within the last 3 years, several organic anion and cation transporters in the kidney have been identified by different cloning techniques. In this review, we describe the mechanisms mediating renal tubular secretion of organic anions and cations, including recent topics in this area.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02479930
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  • 2
    Electronic Resource
    Electronic Resource
    Differential localization of organic cation transporters rOCT1 and rOCT2 in the basolateral membrane of rat kidney proximal tubules (2000)
    Springer
    Histochemistry and cell biology 114 (2000), S. 175-180 
    Details
    ISSN: 1432-119X
    Keywords: Organic cation transporter rOCT1 rOCT2 Kidney Proximal tubule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract. Organic cation transporters play an important role in the secretion of cationic drugs as well as endogenous cationic metabolites in the renal tubules. Immunoblotting showed the presence of organic cation transporter proteins, rOCT1 and rOCT2, in the rat kidney. By immunofluorescence microscopy, rOCT1 was shown to be concentrated in the proximal tubules in the renal cortex. rOCT2, on the other hand, was rich in the proximal tubules in the outer stripe of the outer medulla. Confocal microscopy revealed that both rOCT1 and rOCT2 were localized to the basolateral membranes of these tubule cells. These findings directly show that rOCT1 and rOCT2 are basolateral membrane proteins and are differentially distributed along the proximal tubules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004180000186
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  • 3
    Electronic Resource
    Electronic Resource
    Structural requirements for determining the substrate affinity of peptide transporters PEPT1 and PEPT2 (2000)
    Springer
    Pflügers Archiv 440 (2000), S. 679-684 
    Details
    ISSN: 1432-2013
    Keywords: α- or β-Carbonyl function Cyclic dipeptides Di- and tripeptides Peptide transporters Substrate affinity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. Peptide transporters PEPT1 and PEPT2 transport numerous compounds including small peptides, peptide-like drugs and nonpeptidic compounds such as valacyclovir. PEPT1 and PEPT2 show low and high affinity for most substrates, respectively, but β-lactam antibiotics without an α-amino group are the only known substrates that prefer PEPT1 to PEPT2. The aim of this study was to compare the recognition and affinity of various substrates between rat PEPT1 and rat PEPT2, and to determine the structural requirements influencing the substrate affinity. [14C]Glycylsarcosine uptake by PEPT1- or PEPT2-expressing transfectant was inhibited by di- and tripeptides, but not by amino acids, tetrapeptides or most cyclic dipeptides. All dipeptides and tripeptides examined showed more potent inhibition of [14C]glycylsarcosine uptake via PEPT2 than via PEPT1, irrespective of their charge and structure. Modification of the α-amino group of dipeptides reduced their substrate affinity to both transporters, as compared to unmodified dipeptides, but these dipeptides still showed potent inhibitory effects on PEPT2. Among the nonpeptidic substrates tested, only the eight-amino-octanoic acid displayed stronger inhibition of [14C]glycylsarcosine uptake in PEPT1 than in PEPT2. These findings suggest that α- or β-amino carbonyl function is the key structure responsible for the higher affinity for PEPT2 than for PEPT1.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004240000339
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  • 4
    Electronic Resource
    Electronic Resource
    Peptide Transporter in the Rat Small Intestine: Ultrastructural Localization and the Effect of Starvation and Administration of Amino Acids (1999)
    Springer
    Journal of molecular histology 31 (1999), S. 169-174 
    Details
    ISSN: 1573-6865
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Peptide transporter-1 is a H+/peptide cotransporter responsible for the uptake of small peptides and peptide-like drugs, and is present in the absorptive epithelial cells of the villi in the small intestine (duodenum, jejunum, and ileum). It has been localized to the apical microvillous plasma membrane of the absorptive epithelial cells of the rat small intestine using the immunogold electron microscopic technique. Digital image analysis of the jejunum revealed that the transporter protein was abundant at the tip of the villus and that the amount decreased from the tip of the villus to its base. The effect of dietary administration of amino acids and starvation on the expression of PepT1 in the jejunum was examined by immunoblotting and image analysis of immunofluorescence. Starvation markedly increased the amount of peptide transporter present, whereas dietary administration of amino acids reduced it. The gradient of the transporter protein along the crypt-villus axis was maintained under either condition. These observations show that it is specific to the microvillous plasma membrane and that its expression is regulated by the nutritional condition.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1003515413550
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  • 5
    Electronic Resource
    Electronic Resource
    Decreased Cellular Toxicity of Neomycin in a Clonal Cell Line Isolated from LLC-PK1 (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 573-576 
    Details
    ISSN: 1573-904X
    Keywords: aminoglycoside nephrotoxicity ; apical membrane enzymes ; cell cloning ; neomycin-resistance ; kidney epithelial cell line
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have previously shown in LLC-PK1 cells, that apical membrane enzyme activity was inhibited by aminoglycoside antibiotics (Am. J. Physiol. 254, C251-C257, 1988). In the present study, the relationship between the lethal cytotoxic effect of aminoglycoside and its effect on apical membrane enzyme was examined by establishing aminoglycoside resistant cells. A clonal cell line, LLC-PK1/NRa3, was isolated from parent LLC-PK1 cells in the presence of neomycin. Neomycin inhibited colony formation and increased the number of floating dead cells in parent LLC-PK1 cultures. In contrast, these cytotoxic effects of neomycin were negligible or less pronounced in NRa3 cells, indicating that NRa3 cells were more resistant to neomycin compared with the parent cells. The inhibitory effect of neomycin on apical enzyme activity was significantly weaker in NRa3 cells than in the parent cells. These results suggest that a common mechanism is involved in the aminoglycoside-induced reductions in the apical enzyme activity and in cell viability of LLC-PK1 cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018954204094
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  • 6
    Electronic Resource
    Electronic Resource
    Simulation for population analysis of Michaelis-Menten elimination kinetics (1995)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 23 (1995), S. 205-216 
    Details
    ISSN: 1573-8744
    Keywords: Michaelis-Menten kinetics ; NONMEM ; population pharmacokinetics ; statistical simulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02354272
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  • 7
    Electronic Resource
    Electronic Resource
    Kinetic Analysis of p-Aminohippurate Transport in the OK Kidney Epithelial Cell Line (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 1155-1157 
    Details
    ISSN: 1573-904X
    Keywords: organic anion ; p-aminohippurate ; epithelial transport ; kinetic analysis ; opossum kidney (OK) cell line
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026478301483
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  • 8
    Electronic Resource
    Electronic Resource
    Effects of Intestinal and Hepatic Metabolism on the Bioavailability of Tacrolimus in Rats (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1609-1613 
    Details
    ISSN: 1573-904X
    Keywords: tacrolimus ; bioavailability ; metabolism ; intestine ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Tacrolimus, an immunosuppressive agent, has poor and variable bioavailability following oral administration in clinical use. We investigated the contribution of intestinal metabolism to the first pass effect of tacrolimus in rats. Methods. Tacrolimus was administered intravenously, intraportally or intraintestinally to rats. Blood samples were collected over a 240-min period, and blood tacrolimus concentrations were measured. The extraction ratios of tacrolimus in the intestine and liver were investigated. In addition, the metabolism of tacrolimus in the everted sacs of the small intestine was examined. Results. The rate of absorption of tacrolimus in the intestine was rapid, and tacrolimus was almost completely absorbed after intestinal administration. The bioavailability of tacrolimus was about 40% and 25% after intraportal and intraintestinal administration, respectively, indicating that tacrolimus is metabolized in both the intestine and the liver. In addition, tacrolimus was significantly metabolized in the everted sacs of the rat intestine. Conclusions. The present study suggested that the metabolism of tacrolimus in the intestine contributes to its extensive and variable first pass metabolism following the oral administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011967519752
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  • 9
    Electronic Resource
    Electronic Resource
    Modulation of Organic Cation Transport and Lipid Fluidity by Benzyl Alcohol in Rat Renal Brush-border Membranes (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1069-1072 
    Details
    ISSN: 1573-904X
    Keywords: renal transport ; organic cation ; membrane fluidity ; brush-border membrane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Organic cations are actively transported in renal brush-border membranes (BBM) by the H+/organic cation antiport system. In the present study, we investigated the relationship between membrane fluidity and organic cation transport in the BBM. Methods. The effects of benzyl alcohol, a membrane fluidizing agent, on the organic cation tetraethylammonium (TEA) uptake were studied using renal BBM vesicles isolated from rat kidney. BBM fluidity was assessed by fluorescence polarization technique. Results. H+ gradient-dependent uptake of TEA in BBM vesicles was inhibited by benzyl alcohol in a dose-dependent manner, with an apparent half inhibitory concentration of 18mM. The decrease in fluorescence anisotropy of l,6-diphenyl-l,3,5-hexatriene in BBM, which represents the increase in membrane fluidity, was correlated with the decrease in TEA transport activity. The dissipation rate of H+ gradient, a driving force for organic cation transport in BBM, was increased by benzyl alcohol. In addition, H+ gradient-independent TEA-TEA exchange was also inhibited by benzyl alcohol. These findings indicate that benzyl alcohol inhibits the uptake of TEA by affecting the intrinsic activity of the organic cation transporter and the H+ gradient dissipation rate. Conclusions. The membrane fluidity should be an important determinant for organic cation transport in renal BBM.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016066926269
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  • 10
    Electronic Resource
    Electronic Resource
    Effect of Cyclosporin Analogues and FK506 on Transcellular Transport of Daunorubicin and Vinblastine via P-glycoprotein (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1073-1077 
    Details
    ISSN: 1573-904X
    Keywords: P-glycoprotein ; cyclosporins ; FK506 ; daunorubicin ; vinblastine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. P-glycoprotein-mediated transcellular transport of anticancer agents and the inhibitory effect of cyclosporin analogs and FK506 were investigated. Methods. The transcellular transport of daunorubicin and vinblastine by monolayers of LLC-GA5-COL150 cells which overexpressed P-glycoprotein was measured in the presence and absence of cyclosporins or FK506. Results. Cyclosporins and FK506 inhibited P-glycoprotein-mediated transport of daunorubicin and vinblastine in the order of cyclosporin D, dihydrocyclosporin D 〉 cyclosporin A 〉 FK506 〉 cyclosporin C, dihydrocyclosporin C. The intracellular accumulation of the anticancer agents was highly associated with the transporting function of P-glycoprotein. The inhibitory effect of cyclosporin D was concentration-dependent. The inhibitory effect of the modulators on P-glycoprotein was not correlated with the immunosuppressive activity, but was correlated with their lipophilicity. Conclusions. In the transcellular transport system, lipophilicity may be one of the determinants for the inhibitory effect of various multidrug resistance modulators on the P-glycoprotein-mediated transport.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016019010339
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