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  • 1
    Electronic Resource
    Electronic Resource
    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
    Keywords: hepatic uptake ; albumin receptor-mediated hepatic uptake ; sodium taurocholate ; plasma protein binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062553
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  • 2
    Electronic Resource
    Electronic Resource
    Effect of Plasma Protein Binding on Kinetics of Capillary Uptake and Efflux (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 300-304 
    Details
    ISSN: 1573-904X
    Keywords: protein binding ; capillary clearance ; capillary permeability ; isolated perfused heart preparation ; isradipine ; propafenone ; rate constant for accumulation and washout
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We examined the effect of plasma protein binding on the kinetics of organ accumulation and washout of drugs using the single-pass Kety–Renkin–Crone capillary model. An equation relating the accumulation and washout rate constant (k) with the plasma unbound fraction (f u) was derived. Simulations showed that k was highly dependent on f u if capillary permeability was high but was independent of f u if permeability was low. The effect of plasma protein binding was to increase the rate of tissue accumulation and washout of drug but to decrease the equilibrium amount of drug taken up by the tissue, both effects mediated via a decrease in the volume of distribution. This model was used to analyze published data on the effect of plasma protein binding on the kinetics of accumulation and washout of isradipine and propafenone in the isolated perfused heart preparation. The relationship between k and f u and the directly measured volume of distribution were in accordance with the model. Although more complex models relating k and f u could be proposed, taking into account unequal flows in capillaries, slow dissociation of ligand from protein, and unstirred layer constraints, this simple model appears adequate for describing the effect of f u on myocardial accumulation and washout of isradipine and propafenone.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018959415963
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  • 3
    Electronic Resource
    Electronic Resource
    Effect of Perfusate pH on Reduction of Quinidine Capillary Permeability by Albumin in Isolated Perfused Rat Heart (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1820-1824 
    Details
    ISSN: 1573-904X
    Keywords: isolated perfused heart ; quinidine ; capillary permeability ; perfusate pH ; perfusate albumin concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract It has been suggested that albumin reduces quinidine capillary permeability (PS) in the single-pass perfused heart preparation by reducing paracellular transport of quinidine ions. Using this preparation, we examined the effect of albumin (0.1 per cent) on quinidine PS at perfusate pH’s of 7.1 and 7.9 during uptake of quinidine (19 µM) and also during washout of the drug using a randomized design. Quinidine PS was approximately 16 ml/min/g heart at pH 7.9 and was not altered by the presence of albumin in perfusate. At pH 7.1, in the absence of albumin, quinidine PS was also 16 ml/min/g, but in the presence of albumin (0.1 per cent) PS was reduced significantly to approximately 5 ml/min/g (P 〈 0.001). In the absence of albumin PS was the same at pH 7.1 and 7.9 in spite of a greater degree of ionisation of quinidine at pH 7.1. This suggests that there is significant uptake of ionised quinidine at pH 7.1. The greater effect of albumin on PS at pH 7.1 supports the hypothesis that albumin reduces paracellular transport of quinidine ions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018988005543
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  • 4
    Electronic Resource
    Electronic Resource
    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
    Keywords: taurocholate ; venous equilibrium model ; undistributed sinusoidal model ; distributed sinusoidal models ; dispersion models
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062552
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  • 5
    Electronic Resource
    Electronic Resource
    Kinetic assessment of apparent facilitation by albumin of cellular uptake of unbound ligands (1990)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 18 (1990), S. 121-135 
    Details
    ISSN: 1573-8744
    Keywords: hepatic uptake ; protein binding ; albumin-facilitated hepatic uptake ; taurocholate hepatic uptake ; iopanoic acid hepatic uptake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Previous studies of the effect of albumin on initial uptake of ligands by isolated cell suspensions or cultures found that the apparent uptake for unbound ligand appeared larger in the presence of binding to the albumin than when albumin was absent. Furthermore, when ligand and albumin were increased in a fixed molar ratio, uptake appeared to be competitively inhibited by the excess albumin. We examined the kinetics underlying this apparent facilitation phenomenon by incorporating unbound fraction of ligand in the medium (fU1) into the general model for diffusion between two compartments. The analysis showed that even in the absence of facilitation by albumin, the apparent rate constant for uptake of unbound ligand (k/fu 1) increases as albumin concentration increases but the uptake clearance of unbound ligand remains constant. This theoretical analysis was verified experimentally by measuring the effect of albumin on uptake rates of14C-taurocholate (12, 24, 48, 60, and 96μM, with and without 0.87 mM albumin) in a nonphysiological system consisting of two solutions separated by a cellulose membrane. Moreover, when the taurocholate and albumin concentrations were increased in a fixed molar ratio of 0.06 (taurocholate 12–96 μM, albumin 0.2–1.6 mM), the initial uptake rate exhibited the same nonlinear pattern as the previous studies that used living cells. This pattern was due not to saturation of a putative albumin receptor but simply to the concomitant decrease infU 1 which tended to offset the increase in uptake rate due to the increasing total taurocholate concentration. The model was also used to evaluate published data describing the effect of albumin on the uptake of iopanoic acid by cultured hepatocytes. In accordance with the model,k 1/fu 1 increased as ablumin concentration increased, but uptake clearance was independent of albumin concentration. Therefore, the kinetic pattern found in this and other studies with isolated cell suspensions or cultures argues against a special role for albumin in facilitating cellular ligand uptake.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01063555
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  • 6
    Electronic Resource
    Electronic Resource
    Relationships among duration of infusion, dose, dosing interval, and steady-state plasma concentrations during intermittent intravenous infusions: Studies with metronidazole (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 95-106 
    Details
    ISSN: 1573-8744
    Keywords: intravenous infusion ; plasma concentration-time curves ; infusion rate ; minimum effective plasma concentration ; intermittent infusions ; steady-state ; dosing interval
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Relationships among duration of infusion (T), dose, dosing interval (Τ), maximum and minimum plasma drug concentrations at steady state (Cmax,ssand Cmin,ss, respectively), and the duration of effective plasma concentrations (tD) during multidose intermittent infusion regimens were studied by computer simulation using metronidazoie as a model drug. Pharmacokinetic parameter values for metronidazole were obtained from the literature and the minimum effective plasma concentration (MEC) was taken as 6.0 Μg/ ml. Increasing the infusion period of the dose reduces Cmax,ss, but increases Cmin,ss. If intermittent bolus injection of a given dose of drug results in effective plasma concentrations for the entire dosage interval (i.e., Cmin,ss,bolus〉 MEC), then infusion of that dose over any period (T≤Τ) will also result in effective concentrations for the entire dosage interval. However, if the dosage is such that Cmin,ss,bolus 〈 MEC, the relationships among duration of infusion, dose, dosage interval, and duration of effective plasma concentrations are complex. Therefore a nomogram was developed to allow selection of dose, dosing interval, and infusion period such that Cmax,ss and Cmin,ss could be maintained within a desired range.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059286
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  • 7
    Electronic Resource
    Electronic Resource
    The effect of duration of intravenous infusion on maximum and threshold blood concentrations for drugs exhibiting biexponential elimination kinetics (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 93-107 
    Details
    ISSN: 1573-8744
    Keywords: intravenous infusion ; blood concentration-time curves ; infusion rate ; minimum effective blood concentration ; meperidine ; sulfamethoxazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The relationships among peak blood concentration (C max), the time (t D ) during which blood concentrations are maintained above the minimum effective concentration (C min), and the duration of a constantrate intravenous infusion (T) of a drug exhibiting biexponential pharmacokinetics were simulated by digital computer using Newton iterative procedures. These simulations showed that, in contrast with our previous findings for drugs with monoexponential pharmacokinetics, the relationships are more complex due to the larger number of variables. Therefore, investigation of these relationships for biexponential drugs should be done on a drug by drug basis. Accordingly, meperidine and sulfamethoxazole were chosen as examples of drugs which exhibit biexponential kinetics and were used to determine what errors were involved in using the simpler guidelines for drugs which exhibit monoexponential kinetics as an approximation. These simulations showed the following. (a) The effect ofT onC max may be adequately estimated by using the guidelines for monoexponential kinetics with the elimination half-life $$(t_{\tfrac{1}{2}} )$$ taken as $$t_{\tfrac{1}{2}\lambda 1} $$ provided that λ1 is 20 to 30 times λ1 and that theAUC of the distribution phase (i.e.,C 1/λ 1 comprises greater than about 20% of the totalAUC. (b) As with monoexponential drugs, it is possible to obtain a largert D by infusing the dose compared to that obtained with a bolus, if the value ofC(0)/C min〉2.5. (c) Using the approximation of monoexponential pharmacokinetics to estimate the effect ofC ont D will underestimate botht D and the maximum infusion time, which will just attain theC min unless theAUC of the distribution phase comprises only a very small proportion of the totalAUC. (d) The simulations with meperidine also showed that the nature of the relationship betweent D andT varies depending on whetherC min is maintained in the distribution phase or in both the distribution and elimination phases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059185
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  • 8
    Electronic Resource
    Electronic Resource
    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
    Keywords: plasma protein binding displacement ; unbound fraction ; unbound concentration ; intrinsic clearance ; sodium taurocholate ; sodium oleate ; isolated perfused rat liver
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062383
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  • 9
    Electronic Resource
    Electronic Resource
    Influence of intravenous infusion duration on the tissue drug concentration profile (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 323-334 
    Details
    ISSN: 1573-8744
    Keywords: intravenous infusion ; blood and tissue concentration-time curves ; infusion rate ; minimum effective blood and tissue concentration ; meperidine ; sulfamethoxazole ; ampicillin ; metronidazole
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The influence of intravenous infusion duration of a single dose of drug on the time course of drug concentration in the peripheral compartment of the classical two-compartment pharmacokinetic model was studied by computer simulation. The aim was to illustrate the general relationships among infusion duration T,dose, minimum effective concentration MEC at the effector (tissue) site, maximum tissue drug concentration C2,max,and the duration of effective tissue concentrations tD.tiss for those drugs where there is an equilibration delay between concentration at the effector site and plasma. Simulations of C2,max vs. Tfor meperidine, sulfamethoxazole, ampicillin, and metronidazole showed that, although maximum plasma concentration may decrease markedly with increasing T, C2,max decreased only slightly with increasing T.Simulations of the influence of Ton the duration of effective plasma concentrations tD and tD,tiss of metronidazole showed that for a given T, tD,tiss may be greater than or less than tD,depending on the dose, and that it is possible to obtain effective concentrations in the tissue compartment even though the infusion duration is too long to achieve effective concentrations in plasma. It was found that, depending on the dose, it was possible to cause an increase in tD,tiss compared with bolus administration by increasing the infusion duration of the dose. It was also found that increasing Tcould cause opposite changes in tD and tD,tiss (compared with bolus administration, respectively), e.g., an increase in tD and a decrease in tD,tiss or vice versa, depending on the dose. It should thus be possible to make precise predictions of the influence of Ton drug concentration at the effector site for individual drugs by incorporating effect compartment modeling into the analysis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01106710
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  • 10
    Electronic Resource
    Electronic Resource
    The effect of infusion time on the time course of drug concentration in blood (1980)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 8 (1980), S. 573-582 
    Details
    ISSN: 1573-8744
    Keywords: intravenous infusion ; blood concentration-time curves ; elimination half-life ; infusion rate ; minimum effective blood concentration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We have studied by digital computer simulation the relationships among the rate of intravenous infusion of the dose of a drug, the pharmacokinetic parameters of the drug, the maximum blood drug concentration achieved (Cmax) and the interval (TEff) during which the blood concentration of the drug is maintained above a selected minimum effective concentration (CEff) for the case of single dose administration of a drug with monoexponential pharmacokinetics. It was found that increasing the time during which the dose of the drug is infused results in a much smaller decrease in the maximum blood concentration attained. The interval, TEff, was found to be a function of the ratios infusion time/ drug elimination half-life and zero-time intercept (C0)/ Cff The simulations showed that TEff varies nonlinearly with increasing infusion time. However, the nature of the relationship between TEff and infusion time depends very much on the value of C0/CEff. At low values of C0/CEff, TEff decreased almost linearly with increasing infusion time, but at higher values of C0/ CEff, TEff increased for a time with increasing infusion time. From these simulations, it should be possible to predict whether therapeutically effective blood concentrations of a drug may be achieved with the use of a slower infusion in situations where clinical considerations necessitate that the infusion time of the dose be increased.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01060054
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