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  • 1
    Electronic Resource
    Electronic Resource
    A dispersion model of hepatic elimination: 2. Steady-state considerations-influence of hepatic blood flow, binding within blood, and hepatocellular enzyme activity (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 261-288 
    Details
    ISSN: 1573-8744
    Keywords: hepatic elimination ; hepatic clearance ; availability ; intrinsic clearance ; pharmacokinetics ; dispersion model ; well-stirred model ; tube model ; distributed model ; blood flow ; binding within blood ; hepatocellular enzyme activity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The dispersion model of hepatic elimination is based on the distribution of residence times of blood elements within the liver. The model has two asymptotic solutions corresponding to the “wellstirred” model (complete mixing of blood elements) and the “parallel-tube” model (no variation in residence times of blood elements). The steady-state form of the dispersion model relevant to pharmacokinetic analysis is developed and explored with respect to changes in blood flow, in binding within blood, and in hepatocellular enzyme activity. Literature data are used to evaluate discrepancies among the predictions of the dispersion, well-stirred, and tube models. It is concluded that the dispersion model is consistent-with the data. The limitations of steady-state perfusion experiments to estimate the residence time distribution of blood elements within the liver are considered.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01106707
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance (1977)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 5 (1977), S. 625-653 
    Details
    ISSN: 1573-8744
    Keywords: hepatic drug clearance ; models ; blood flow ; drug binding ; hepatocelluSar enzymatic activity ; intrinsic clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Two commonly used models of hepatic drug clearance are examined. The “well-stirred” model (model I) views the liver as a well-stirred compartment with concentration of drug in the liver in equilibrium with that in the emergent blood. The “parallel tube” model (model II) regards the liver as a series of parallel tubes with enzymes distributed evenly around the tubes and the concentration of drug declines along the length of the tube. Both models are examined under steady-state considerations in the absence of diffusional limitations (cell membranes do not limit the movement of drug molecules). Equations involving the determinants of hepatic drug clearance (hepatic blood flow, fraction of drug in blood unbound, and the hepatocellular enzymatic activity) and various pharmacokinetic parameters are derived. Similarities and differences between the models are explored. Although both models predict similar hepatic drug clearances under a variety of conditions, marked differences between them become apparent in their predictions of the influence of changes in the determinants of drug clearance on various pharmacokinetic parameters.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059688
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    A dispersion model of hepatic elimination: 1. Formulation of the model and bolus considerations (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 227-260 
    Details
    ISSN: 1573-8744
    Keywords: dispersion model ; hepatic elimination ; bolus ; well-stirred model ; parallel-tube model ; distributed model ; protein binding ; hepatic cellular activity ; cellular permeability ; blood flow ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A dispersion model of hepatic elimination, based on the residence time distribution of blood elements within the liver, is presented. The general rate equations appropriate for describing the hepatic output concentration of a tracer solute are derived. Particular consideration is given to events following a bolus input dose of a tracer. The model is shown to be compatible with the known hepatic architecture and hepatic physiology. The model has been fitted to hepatic outflow data for red blood cells, albumin, and other noneliminated solutes. The experimental data suggest a high degree of dispersion of blood elements within the liver. The model has also been used to evaluate the effects of changes in enzyme activity, hepatic cell permeability, blood flow, and protein binding on the outflow concentration vs. time profiles of solutes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01106706
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Protein binding and hepatic clearance: Studies with tolbutamide, a drug of low intrinsic clearance, in the isolated perfused rat liver preparation (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 225-243 
    Details
    ISSN: 1573-8744
    Keywords: tolbutamide ; hydroxytolbutamide ; binding ; clearance ; extraction ratio ; perfused rat liver preparation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The influence of altered drug binding on the hepatic elimination of tolbutamide, a drug of low intrinsic clearance, and on the formation of its metabolite, hydroxytolbutamide, was examined under linear conditions at steady state in the isolated in situsingle-pass perfused rat liver preparation, with perfusate flow fixed at 15 ml/min. The fraction of tulbutamide unbound in the perfusate was varied (from 0.06 to 1.0) by either varying the perfusate concentration of albumin or using albumin of different animal species. The intrinsic clearance of tolbutamide varied fourfold between preparations (0.08–0.36 ml/min/g liver). Within each preparation the data were normalized to observations with a perfusate containing no protein. Both the extraction ratio (and clearance) of tolbutamide and the fraction of tulbutamide appearing as hydroxytolbutamide in effluent perfusate, a measure of hepatic metabolism, were directly proportional to the fraction of tolbutamide unbound in the perfusate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061866
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    Paper (German National Licenses)
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  • 5
    Electronic Resource
    Electronic Resource
    Binding of Sulfonamides to Carbonic Anhydrase: Influence on Distribution Within Blood and on Pharmacokinetics (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 203-209 
    Details
    ISSN: 1573-904X
    Keywords: pharmacokinetics ; carbonic anhydrase ; sulfonamides ; binding ; erythrocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Four new aromatic sulfonamides were synthesized and purified by standard techniques. Two were unsubstituted, primary sulfonamides and two possessed substituents on the sulfonamide nitrogen. The affinity of the inhibitors for the enzyme carbonic anhydrase was determined in terms of the inhibitory potency, which was found to be dependent on the presence of an unsubstituted sulfonamide group. Binding studies were performed in erythrocyte suspensions using a range of concentrations and the unbound, extracellular concentrations were determined by high-performance liquid chromatographic (HPLC) assay. The dissociation constant of binding and the total binding capacity of the erythrocytes were estimated by nonlinear regression using a two-site binding model. The affinity of the compounds for erythrocytes reflected their inhibitory potency against the enzyme. Binding to plasma proteins was more dependent on lipophilicity and pK a and was stronger for the substituted sulfonamides. Pharmacokinetic studies in rats showed that the unsubstituted sulfonamides with a high affinity for carbonic anhydrase in erythrocytes have longer half-lives and lower clearance values than the substituted sulfonamides which were more strongly bound to plasma proteins. However, comparison of unbound clearance values showed that the variations in molecular structure, which produced differences in carbonic anhydrase binding and in distribution, also produced variations in susceptibility to elimination processes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015957315462
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    Paper (German National Licenses)
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