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  • 1
    Electronic Resource
    Electronic Resource
    Kinetic analysis of the dose-dependent hepatic handling of 1-anilino-8-naphthalene sulfonate in rats (1990)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 18 (1990), S. 313-333 
    Details
    ISSN: 1573-8744
    Keywords: hepatic transport ; 1-anilino-8-naphthalene sulfonate (ANS) ; dose dependency ; saturable tissue binding ; organic anions ; cytosolic protein ; nonlinear pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The dose dependency in the hepatic transport of an anionic fluorescent dye, 1-anilino-8-naphthalene sulfonate (ANS), was investigated by measuring the plasma disappearance and biliary excretion in rats. Bulk of the administered ANS distributed into the liver at 10 min after iv bolus injection. The plasma disappearance curves of ANS were then kinetically analyzed based on a two-compartment model, in which the ligand is eliminated only from the peripheral compartment (liver compartment). The total body clearance (CLtot) decreased with increasing dose of ANS. That is, the values of CLtot were 4.06 and 1.98 ml/min/per kg at the doses of 3 and 100 Μmol/kg, respectively. The clearances of the uptake and sequestration processes (CLup and CLseq, respectively) for a total ligand were constant irrespective of dose, while the efflux clearance (CLeff) for a total ligand was increased by twofold with increasing dose. A mechanism for the increase in the CLeff value might be explained by a saturation of the ANS binding to the intracellular proteins. The hepatocellular distribution and the binding of ANS to cytosolic proteins were then determined. ANS mainly distributed to the cytosol fraction, and the unbound fraction in the cytosol increased from approximately 0.04 to 0.09 when the cytosolic concentrations of ANS increased from 40 to 900 ΜM, respectively. In,spite of such increase in the unbound fraction in the cytosol, the CLseq values remained unchanged with increasing dose, suggesting that the saturation of sequestration clearance for unbound ANS might occur. Furthermore, the plasma disappearance curves of ANS at various doses were simultaneously analyzed based on three nonlinear kinetic models: Model I is a model incorporating both saturable intracellular binding and saturable sequestration; Model II is a model incorporating only saturable intracellular binding; Model III is the model incorporating only saturable sequestration. Goodness- of- fit evaluated by AIC value was best for Model I. Taken together, the nonlinearity in the plasma clearance of ANS was confirmed to be attributed to saturation of both its binding to cytosolic proteins and sequestration process.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062271
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Analysis of Nonlinear and Nonsteady State Hepatic Extraction with the Dispersion Model Using the Finite Difference Method (1998)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 26 (1998), S. 495-519 
    Details
    ISSN: 1573-8744
    Keywords: nonlinear pharmacokinetics ; dispersion model ; multiple indicator dilution ; hepatic clearance ; transit time distribution ; finite difference method ; nonlinear partial differential equation ; computer simulation ; BQ-123
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A numerical calculation method for dispersion models was developed to analyze nonlinear and nonsteady hepatic elimination of substances. The finite difference method (FDM), a standard numerical calculation technique, was utilized to solve nonlinear partial differential equations of the dispersion model. Using this method, flexible application of the dispersion model becomes possible, because (i) nonlinear kinetics can be incorporated anywhere, (ii) the input function can be altered arbitrarily, and (iii) the number of compartments can be increased as needed. This method was implemented in a multipurpose nonlinear least-squares fitting computer program, Napp (Numeric Analysis Program for Pharmacokinetics). We simulated dilution curves for several nonlinear two-compartment hepatic models in which the saturable process is assumed in transport or metabolism, and investigated whether they could definitely be discriminated from each other. Preliminary analysis of the rat liver perfusion data of a cyclic pentapeptide, BQ-123, was performed by this method to demonstrate its applicability.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1023294632129
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  • 3
    Electronic Resource
    Electronic Resource
    Renal Clearance of a Recombinant Granulocyte Colony-Stimulating Factor, Nartograstim, in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1466-1469 
    Details
    ISSN: 1573-904X
    Keywords: granulocyte colony-stimulating factor ; nonlinear pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To clarify the role of the kidney in the elimination of a recombinant human granulocyte colony-stimulating factor, nartograstim, we have investigated its pharmacokinetics in rats with renal failure. Methods. The steady-state clearance (CLss) were determined by the intravenous infusion for 4 hr to unilateral renally-ligated and cisplatin-treated rats, whose renal functions were about 50 and 10 % of controls, respectively. Results. CLss of nartograstim (27 ml/hr/kg) in the renally-ligated rats at a high infusion rate was significantly lower (25%) than in control rats (p〈0.05). CLss in these rats, at a low infusion rate was 95 ml/hr/kg, 14 % lower than in control rats. The saturable CLss in these rats, 68 ml/hr/kg, was not significantly different from control rats (75 ml/hr/kg, p〉0.05). Also, CLss in cisplatin-treated rats with extensive renal failure, at a high infusion rate, decreased to 57 % of controls. Furthermore, the total body clearances (CLtot) of nartograstim after bolus intravenous administration to renally-ligated and cisplatin-treated rats were reduced to 33–49 % of controls. Conclusions. These results suggest that the kidney may be responsible for 40– 50 % of the nonsaturable clearance of nartograstim. Thus, the kidney should make a major contribution to the elimination of nartograstim when rats are given a high dose of nartograstim, which saturates the receptor-mediated clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016227202781
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Analysis of Nonlinear Hepatic Clearance of a Cyclopentapeptide, BQ-123, with the Multiple Indicator Dilution Method Using the Dispersion Model (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 103-109 
    Details
    ISSN: 1573-904X
    Keywords: nonlinear pharmacokinetics ; dispersion model ; multiple indicator dilution method ; BQ-123 ; hepatic transport ; finite difference method
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To bridge in vitro, in situ and in vivo kinetic analyses of the hepatic clearance of a cyclopentapeptide, BQ-123, by using dispersion models that assume nonlinear pharmacokinetics. Methods. Rat livers were perfused by the multiple indicator dilution method with doses of BQ-123 ranging from 1-1000 μg. The outflow dilution curves were fitted to a two-compartment dispersion model that was solved numerically by the finite difference method. Further, in vivo plasma concentrations of BQ-123 after bolus injection were analyzed with a hybrid physiological model that incorporates the hepatic dispersion model. Results. The calculated Michaelis-Menten constants (Km = 12.0 μM, Vmax = 321 pmol/min/106 cells, Pdif = 1.2 μl/min/106 cells) were comparable to those obtained previously from the in vitro isolated hepatocyte experiment (Km = 9.5 μM, Vmax = 517 pmol/min/106 cells, Pdif =1.1 μl/min/106 cells). The plasma concentrations of BQ-123 at doses of 1-25 mg/kg were explained well by the hybrid physiological model. Conclusions. These results suggest that carrier-mediated transport on the sinusoidal membrane was responsible for the in vivo hepatic elimination of BQ-123.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018831131119
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    Paper (German National Licenses)
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