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  • 1
    Digitale Medien
    Digitale Medien
    The pharmacokinetics and metabolism of the anilide local anaesthetics in neonates (1978)
    Springer
    European journal of clinical pharmacology 13 (1978), S. 143-152 
    Details
    ISSN: 1432-1041
    Schlagwort(e): Lignocaine ; pharmacokinetics ; neonates ; metabolism ; renal excretion ; plasma concentrations
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie , Medizin
    Notizen: Summary The pharmacokinetics and metabolism of lignocaine in premature neonates was studied after subcutaneous administration. The collection of serial urine together with a limited number of blood samples from neonates enabled simultaneous computer fitting of data to a pharmacokinetic model. The disposition kinetics of lignocaine in four neonates were compared with similar data reported for adults. Neonates had prolonged t1/2 (neonate mean: 3.16 h; adult mean: 1.80 h), and an increased total volume of distribution (neonate mean: 2.75 l/kg; adult mean: 1.11 l/kg) compared with adults. Total plasma clearance (Cltp) normalised on body weight showed no significant difference between neonates (mean: 0.610 l/h/kg) and adults (mean: 0.550 l/h/kg). The urinary excretion of lignocaine and several of its metabolites was studied in 8 neonates and 11 adults. Neonates were shown to excrete much more unchanged lignocaine (mean: 19.67%) compared with adults (mean: 4.27%) and the proportion of the dose excreted as 4-hydroxyxylidine is considerably reduced in neonates (neonate mean: 8.89%; adult mean: 63.78%). The use of the two pharmacokinetic parameters, t1/2 and Cltp, as indices of drug elimination ability are discussed.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00609759
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  • 2
    Digitale Medien
    Digitale Medien
    Lack of linear correlation between hepatic ligand uptake rate and unbound ligand concentration does not necessarily imply receptor-mediated uptake (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 397-411 
    Details
    ISSN: 1573-8744
    Schlagwort(e): hepatic uptake ; albumin receptor-mediated hepatic uptake ; sodium taurocholate ; plasma protein binding
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract Previous studies of the hepatic uptake of several albumin-bound ligands, using constant and variable albumin concentrations, were interpreted as being inconsistent with the traditional mechanism of uptake, defined as an uptake rate directly proportional to unbound ligand concentration, and led to the formulation of the albumin receptor theory of hepatic uptake. Because other experimental designs have failed to confirm the albumin receptor theory, we reexamined, using the isolated perfused rat liver preparation, the traditional uptake mechanism under the conditions used in the original studies, of constant and variable albumin concentration. Livers (n=6) were perfused in randomized sequence with 10 different solutions containing 24-14C-taurocholate in a single-pass design. Five solutions contained fixed albumin (0.1 mM) and variable taurocholate (3–48 μM) concentrations, and five maintained the taurocholate-albumin ratio fixed at 0.06; absolute concentrations of taurocholate varied from 3–48 μM, and of albumin from 0.05–0.08 mM. At constant albumin concentration in hepatic inflow, elimination rate of taurocholate was linearly related to both total (Cin) and unbound (Cin,u) taurocholate concentration in hepatic inflow, indicating first-order elimination kinetics. When taurocholate and albumin were increased in hepatic inflow in a fixed molar ratio, taurocholate uptake rate was not linearly related to Cin,u but was still consistent with the traditional uptake mechanism. Moreover, the apparent saturation of taurocholate uptake by added albumin was consistent with the reduction in unbound fraction (fu) in accordance with the traditional uptake mechanism. This study shows that although the traditional uptake mechanism dictates that ligand uptake rate is linearly related to unbound ligand concentration within the liver, uptake rate need not necessarily be linearly related to Cin,u.. Therefore, experiments in which lack of a linear relationship between uptake rate and Cin,u is found do not necessarily imply receptor-mediated uptake.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01062553
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  • 3
    Digitale Medien
    Digitale Medien
    Effect of plasma protein binding on elimination of taurocholate by isolated perfused rat liver: Comparison of venous equilibrium, undistributed and distributed sinusoidal, and dispersion models (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 377-396 
    Details
    ISSN: 1573-8744
    Schlagwort(e): taurocholate ; venous equilibrium model ; undistributed sinusoidal model ; distributed sinusoidal models ; dispersion models
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract In the past, various models have been developed to allow better characterization of the hepatic elimination of substrates from plasma. In this study we investigated the applicability of the venous equilibrium, undistributed sinusoidal, several distributed sinusoidal, and dispersion models to the steady state elimination of sodium taurocholate by the isolated perfused rat liver. Rat livers were perfused with 24-14C- taurocholate (sodium salt) at a concentration of 25 μM (specific activity 500 μCi/mmole) in a single-pass design (n=7) or at a rate of 0.5 μmol/min (specific activity 40 μCi/mmole) into the portal vein in a recirculating design (n=5). In single-pass experiments, the changes in hepatic venous outflow concentration (C0) with changes in unbound fraction of taurocholate (fu) from 0.09 to 1.0 were fitted better by the venous equilibrium model, by the dispersion model, and by a distributed model in which heterogeneity in both hepatic blood flow (Q) and intrinsic clearance (CLint) was defined by separate density functions. The very large value of dispersion number (Dn〉107) yielded by the dispersion model is consistent with a high degree of axial mixing of blood within sinusoids. The large coefficients of variation (0.7–232) for the density functions describing the transverse heterogeneity of Q and CLint obtained with the Q/CLint -distributed model were consistent with a large degree of heterogeneity in Q and CLint within the liver. In recirculation experiments. the steady state unbound concentration of taurocholate in the reservoir (Cuss) was independent of fu (range 0.05–0.9). This finding was not predicted by the undistributed sinusoidal model, but was in keeping with the venous equilibrium model, with the dispersion model, and with the Q/CLint- distributed model. Therefrore, there is no need to invoke cell surface-mediated dissociation of albumin-ligand complexes in hepatic taurocholate uptake. As the dispersion and Q/CLint- distributed models are conceptually plausible and operationally accurate, it may be time to relinquish the venous equilibrium model, which, though operationally accurate, is conceptually flawed.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01062552
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  • 4
    Digitale Medien
    Digitale Medien
    Effect of a protein binding change on unbound and total plasma concentrations for drugs of intermediate hepatic extraction (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 529-542 
    Details
    ISSN: 1573-8744
    Schlagwort(e): plasma protein binding displacement ; unbound fraction ; unbound concentration ; intrinsic clearance ; sodium taurocholate ; sodium oleate ; isolated perfused rat liver
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Chemie und Pharmazie
    Notizen: Abstract For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu b )on steady state total (C b )and unbound (Cu b )blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL int ).For a substance of very low CL int ,if fu b changes, C t will change and Cu b will remain constant, whereas if CL int isvery high, Cu b will change and C b will remain constant.The present study defines the effects of a change in fu b on C b and Cu b over the whole CL int range. Computer simulations were undertaken which predicted that, for a given change in fu b ,absolute and relative changes in C b would decreasenonlinearly with increasing CL int, twhile the relative change in Cu b would increasewith CL int .The absolute change in Cub would be independent of CL int .Significant changes in Cb and Cu b would be observed at intermediate values of CL int not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in fu b of sodium taurocholate a substance with intermediate CL int (such that at fu b =0.27,hepatic extraction ratio=0.71) induced by concurrent administration of sodium oleate. Sodium 24- 14 C-taurocholate (specific activity 52 μCi/mmol) was infused into the reservoir in a recycling system at 30 μmol/hr for 105 min (n=6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu b fell promptly by 55% (0.27–0.12). There was a relative increase of taurocholate C b of 22.7% and a relative decrease in Cu b of 45.4%, in accordance with the simulations (p〈0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF01062383
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