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  • 1
    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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  • 2
    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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  • 3
    Electronic Resource
    Electronic Resource
    Transepithelial Transport of Levofloxacin in the Isolated Perfused Rat Kidney (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 236-241 
    Details
    ISSN: 1573-904X
    Keywords: quinolones ; transport ; renal secretion ; isolated perfused kidney ; moment analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The transepithelial transport of levofloxacin was evaluatedin the isolated perfused kidney to investigate its renal secretorymechanisms. Methods. Levofloxacin was instantaneously administered into the renalartery together with inulin and Evans blue-labeled albumin, and thesingle-pass dilution curves of the renal venous and urinary outflowwere determined in the absence or presence of various compounds.Kinetic parameters were computed based on non-compartmentmoment analysis. Results. The ratio of fractional excretion to filtration fraction (FE/FF)for levofloxacin was 2.99 ± 0.18, indicating the involvement of tubularsecretion. In the presence of cimetidine and quinolones, the FE/FF oflevofloxacin was significantly decreased and the transepithelial meantransit time (¯Tcell) of levofloxacin was prolonged. The ¯Tcell showed anegative correlation with renal secretion of levofloxacin, while thevolume of distribution of levofloxacin showed no correlation. Conclusions. Transport on the brush-border membrane plays adetermining step in the renal secretion of levofloxacin, and cimetidineand quinolones interact with levofloxacin transport on thebrush-border membrane.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007533817835
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  • 4
    Electronic Resource
    Electronic Resource
    Kinetic Analysis of Tetraethylammonium Transport in the Kidney Epithelial Cell Line, LLC-PK1 (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1236-1240 
    Details
    ISSN: 1573-904X
    Keywords: organic cation ; epithelial transport ; LLC-PK1 ; kinetic model ; levofloxacin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The aims of this study were to establish a kinetic means of analyzing the membrane transport of organic cations in renal epithelial cells, and to simultaneously evaluate drug interactions in apical and basolateral membranes. Methods. Tetraethylammonium (TEA) transport was measured using LLC-PK1, cell monolayers grown on microporous membrane filters. After incubating the cells with unlabeled TEA or other drugs, apical or basolateral medium was changed to that containing labeled TEA, and transcellular transport and cellular accumulation were measured. Clearance from apical medium to cells (CL12), cells to apical medium (CL21), cells to basolateral medium (CL23) and basolateral medium to cells (CL32) were calculated based on a three compartment model. Results. TEA was accumulated progressively in the monolayers from the basolateral side and was transported unidirectionally to the apical side. CL32 was greater than CL12 and CL23 was greater than CL21. Therefore, the rate limiting step of TEA transport from the basolateral to the apical medium was the cell-to-apical step. Co-incubation of TEA with procainamide decreased the transport parameters of TEA, CL12, CL21 and CL32, whereas that with levofloxacin decreased only CL12 and CL21, not affecting the parameters in basolateral membranes. Conclusions. Using a simple model, we analyzed the transport of organic cation in kidney epithelial cell line, LLC-PK1 This method can be useful for the analysis of cation transport and drug interactions in the apical and basolateral membranes of renal tubules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012119210434
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  • 5
    Electronic Resource
    Electronic Resource
    Effect of Neutral Endopeptidase Inhibition on the Natriuresis and Renal Clearance of Atrial Natriuretic Peptide in Perfused Rat Kidney (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1499-1502 
    Details
    ISSN: 1573-904X
    Keywords: atrial natriuretic peptide ; neutral endopeptidase ; perfused kidney ; phosphoramidon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011934512483
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  • 6
    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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  • 7
    Electronic Resource
    Electronic Resource
    Distribution Characteristics of Levofloxacin and Grepafloxacin in Rat Kidney (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 534-539 
    Details
    ISSN: 1573-904X
    Keywords: levofloxacin ; grepafloxacin ; quinolone antibacterial drugs ; renal transport ; tissue distribution ; cortical slices
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To elucidate the renal distribution of quinolones, we examined the uptake of levofloxacin and grepafloxacin in vivo and in rat renal cortical slices. Methods. The plasma and various tissue concentrations of levofloxacin and grepafloxacin were measured after a bolus injection in rats, and tissue uptake clearance was calculated. Transport characteristics of quinolones in rat renal cortical slices were evaluated. Results. The tissue distribution of levofloxacin and grepafloxacin in the kidney was greater than in any other tissue, and the tissue uptake clearances of levofloxacin and grepafloxacin in the kidney cortex were 1.2 and 4.6 ml/min/g tissue, respectively. The uptake of levofloxacin and grepafloxacin in rat renal cortical slices was concentrative, as indicated by slice/medium ratios of 2.3 and 9.6 at 60 min, respectively. The uptake of levofloxacin and grepafloxacin in rat renal cortical slices showed saturation, and was significantly inhibited in the presence of quinidine (p 〈 .05), but not of tetraethylammonium or /p-aminohippurate. Conclusions. Renal distribution of levofloxacin and grepafloxacin may be mediated by a specific transport system for quinolones, distinct from the organic cation and organic anion transport systems in the kidney.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018871029244
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  • 8
    Electronic Resource
    Electronic Resource
    N-terminal Halves of Rat H+/Peptide Transporters Are Responsible for Their Substrate Recognition (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 15-20 
    Details
    ISSN: 1573-904X
    Keywords: peptide transporters ; chimeras ; intestinal absorption ; renal reabsorption ; β-lactam antibiotics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Peptide transporters PEPT1 and PEPT2 differ substantiallyin their substrate affinity and recognition. The aim of this study is todefine the structural domains which influence the functionalcharacteristics of both transporters Methods. Two kinds of chimeric peptide transporters (PEPT-N1C2and PEPT-N2C1) were constructed, and their functional characteristicswere compared with those of wild-type transporters in stabletransfectants. Results. PEPT-N1C2, the N-terminal half of rat PEPT1 and theC-terminal half of rat PEPT2, and the reciprocal chimera PEPT-N2C1were functionally expressed in LLC-PK1 cells. The pH-profiles of [14C]glycylsarcosine uptake by PEPT-N1C2 and PEPT-N2C1 were close tothose of PEPT1 and PEPT2, respectively. Substrate recognition forPEPT-N1C2 and PEPT-N2C1 was also similar to that of PEPT1 andPEPT2, respectively. However, substrate affinities for PEPT-N1C2were higher than those for PEPT1, although those for PEPT-N2C1 andPEPT2 were comparable. Conclusions. These results indicate that functional regions which areassociated with the extracellular pH changes and are responsible forsubstrate recognition of PEPT1 and PEPT2 may be located in theN-terminal halves of the proteins. In addition, it is suggested that thedomain to affect the substrate affinity exists in the C-terminal as wellas in the N-terminal half of rat PEPT2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007554105597
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  • 9
    Electronic Resource
    Electronic Resource
    Clearance Mechanisms of Atrial and Brain Natriuretic Peptides in Rats (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 60-64 
    Details
    ISSN: 1573-904X
    Keywords: atrial natriuretic peptide ; brain natriuretic peptide ; clearance receptor ; neutral endopeptidase ; phosphoramidon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To assess clearance mechanisms of atrial and brain natriuretic peptides in the circulation, we examined the effects of a neutral endopeptidase (NEP) inhibitor and a clearance receptor ligand on plasma concentrations of the peptides in normal rats. Plasma concentrations of endogenous α-rat atrial natriuretic peptide (α-rANP) were not significantly elevated by intravenous infusion of a NEP inhibitor, phosphoramidon, but were elevated threefold by intravenous infusion of a clearance receptor ligand, des(Gln18-Gly22)-rANP(4−23)-NH2 [C-ANF(4−23)]. On the other hand, the clearance of α-rANP given intravenously at the pharmacological dose, 600 pmol/ min/kg for 2 min, was decreased to one-third by the administration of phosphoramidon, although the administration of C-ANF(4−23) did not significantly decrease the clearance. The clearance of rat brain natriuretic peptide (rBNP) given at 600 pmol/min/kg for 2 min was approximately 38% lower than that of α-rANP. The effect of phosphoramidon on the clearance of rBNP was not significant and was similar to that of C-ANF(4−23). These results suggest that clearance receptor is involved in the clearance of the physiological levels of α-rANP and that NEP plays a major role in the clearance of a pharmacological dose of α-rANP, at which clearance receptors are thought to be saturated, and also indicate a pharmacokinetic difference between α-rANP and rBNP.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018941626731
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  • 10
    Electronic Resource
    Electronic Resource
    Natriuretic Peptide-Potentiating Actions of Neutral Endopeptidase Inhibition in Rats with Experimental Heart Failure (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1726-1730 
    Details
    ISSN: 1573-904X
    Keywords: arterio-venous fistula ; atrial natriuretic peptide ; heart failure ; myocardial infarction ; neutral endopeptidase ; phosphoramidon
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We developed a rat model of heart failure induced by myocardial infarction (MI) which preserves responsiveness to exogenously administered natriuretic peptide, and investigated the potentiating action of neutral endopeptidase (NEP) inhibition on the renal response to endogenous natriuretic peptide in MI rats, comparing with that in the established cardiac-failing model with arterio-venous fistula (AVF). The endogenous plasma concentration of α-rat atrial natriuretic peptide (α-rANP) in the MI rat was 6.4-fold higher than that in the normal rat, and intravenous infusion of phosphoramidon (165 nmol/min/kg), an NEP inhibitor, induced larger increases in circulating α-rANP levels and natriuresis in MI rats than in normal controls. The maximal natriuretic effect of phosphoramidon (165 nmol/ min/kg) was equal to that of exogenously administered α-rANP (100 pmol/min/kg) in MI rats, whereas plasma α-rANP concentration under NEP inhibition was much lower than that after administration of α-rANP. The endogenous α-rANP levels in AVF rats were as high as those in MI rats. However, the natriuretic effect of phosphoramidon was less in AVF rats than in MI rats, which was consistent with the decreased natriuretic activity observed with administration of exogenous to α-rANP in the AVF rat. These results indicate that the natriuretic effect of NEP inhibition is dependent on elevated endogenous α-rANP levels in cardiac-failing rats, but cannot be accounted for simply in terms of the increase in circulating α-rANP levels. Endogenous natriuretic peptide-mediated natriuresis under NEP inhibition also appears to correlate with the responsiveness to the exogenously administered peptide.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018907215113
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