Library

X
feed icon rss

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Electronic Resource
    Electronic Resource
    Cell killing action of cell cycle phase-non-specific antitumor agents is dependent on concentration-time product (1988)
    Springer
    Cancer chemotherapy and pharmacology 21 (1988), S. 185-190 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Based on a pharmacokinetic model proposed by Jusko, which assumes that the cell killing action of cell cycle phase-non-specific agents occurs as a bimolecular reaction depending on drug concentration and cell density, we derived a cell kill kinetic equation for these drugs, including the decomposition constant in culture medium. This equation revealed that the cell killing activity of these drugs depends on the value of concentration x exposure time or the area under the drug concentration-time curve (AUC). It was also clarified that the curves for concentration-exposure time necessary for 90% cell kill on a log scale simulated on the basis of the equation differ according as whether drugs are stable or unstable in the culture medium, being expected to be linear with a slope of-1 in the former case, and to take the form of an asymptotic curve in the latter. For three cell cycle phase-non-specific agents, mitomycin C (MMC), 1-(4-amino-2-methylpyrimidine-5-yl)-methyl-3-(2-chloroethyl)3-nitrosourea hydrochloride (ACNU), and nitrogen mustard (HN2), we assessed the concentrations necessary for 90% cell kill (IC90) with various exposure times and the degradation rate constants under the culture conditions used. MMC was quite stable during the incubation, while ACNU and HN2 were unstable. When IC90's and exposure times were plotted on the above-mentioned graph, a linear relationship with a slope of-1 was seen for MMC, while for ACNU and HN2 the anticipated asymptotic curves resulted. We also ascertained that the decomposition constants for ACNU and HN2 expected on the basis of these curves showed a good agreement with the corresponding experimentally observed values. These results indicate that the cell killing action of cell cycle phase-non-specific drugs can be well described by a pharmacodynamic model and equation employing their decomposition constants and are dependent on the concentration-time product.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00262767
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 2
    Electronic Resource
    Electronic Resource
    Theoretical consideration of drug distribution kinetics in a noneliminating organ: Comparison between a “homogeneous (well-stirred)” model and “nonhomogeneous (tube)” model (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 265-287 
    Details
    ISSN: 1573-8744
    Keywords: drug distribution kinetics ; noneliminating organ ; homogeneous model ; well-stirred model ; nonhomogeneous model ; tube model ; tissue-to-plasma partition coefficient ; tissue-to-blood partition coefficient ; physiological pharmacokinetics ; redistribution clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Drug distribution kinetics in a noneliminating organ or tissue has been mathematically examined. The homogeneous (well-stirred) model regards the noneliminating organ or tissue as a homogeneous compartment in which the drug is equilibrated with that in the blood leaving the organ or tissue. The nonhomogeneous (tube) model views the noneliminating organ or tissue as comprising a number of parallel cylindrical tubes containing binding sites distributed homogeneously along these tubes. These two models are examined, considering the pseudo-distribution equilibrium phase after bolus injection and a linear binding condition. Although both models predict a similar tissue distribution under a variety of conditions, significant differences exist in the predictions of various pharmacokinetic parameters as a function of the drug distribution, such as blood flow, organ volume, slope of the terminal phase, and the tissue-to-blood partition coefficients. The predictability and limitations of these two models are explored. Distribution characteristics of the two models are also examined for adriamycin, actinomycin D, tetrachlorobiphenyl, hexachlorobiphenyl, digoxin, and ethoxybenzamide; no difference is observed. It is concluded that the assumption of a homogeneous (well-stirred) compartment is suitable for describing the drug distribution kinetics of these drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01065656
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Prediction of the disposition of nine weakly acidic and six weakly basic drugs in humans from pharmacokinetic parameters in rats (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 477-492 
    Details
    ISSN: 1573-8744
    Keywords: animal scaleup ; rat ; human ; weakly acidic drug ; weakly basic drug
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Various pharmacokinetic parameters—disposition half-life, t 1/2,z, metabolic clearance CLm, volume of distribution V, intrinsic clearance of unbound drug CLut, and unbound volume of distribution of tissues (distributive tissue volume / fraction of drug in tissue unbound, VT/fuT—are compared in rat and human for nine weakly acidic drugs, phenytoin, hexobarbital, pentobarbital, phenylbutazone, warfarin, tolbutamide, valproate, phenobarbital, and amobarbital, and six weakly basic drugs, quinidine, chlorpromazine, propranolol, pentazocin, antipyrine, and diazepam. With regard to all parameters, statistically significant correlations are obtained when parameters are plotted on a log-log plot. Correlation coefficients between the intrinsic parameters (CLuint or VT/fuT) were higher than those between the hybrid parameters (t1/2,z, CLm, or V). In general, these drugs were metabolized ten times more rapidly in rat than in human. With regard to the tissue distribution of these drugs, there was little difference between rat and human. Predictions of CLm, V, and t1/2, in humans using rat data were successful for most drugs, with a few marked exceptions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059331
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 4
    Electronic Resource
    Electronic Resource
    Saturable Process Involved in Active Efflux of Vincristine as a Mechanism of Multidrug Resistance in P388 Leukemia Cells (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 690-696 
    Details
    ISSN: 1573-904X
    Keywords: multidrug resistance ; active efflux ; vincristine ; kinetic analysis ; carrier-mediated transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Kinetic analysis of vincristine (VCR) efflux in multidrug-resistant and parental P388 leukemia cells was performed to investigate the difference in activity between the two cell lines. Efflux velocities of VCR were directly determined from the slope of the initial release of drug induced by resuspending the preloaded cells in VCR-free medium, representing unidirectional efflux from intracellular free or loosely bound drug pools. Further, the equilibrium binding of VCR to whole-cell homogenates was analyzed by ultrafiltration to estimate intracellular unbound drug concentrations. A two-site binding model was found to fit the data best for both cell lines, and depletion of ATP by the addition of apyrase decreased binding. The binding parameters were similar between the two cell lines. A Hofstee plot of efflux demonstrated the existence of both linear and saturable transport of VCR in both cell lines. The greater maximum velocity observed with VCR efflux in the resistant cells suggests that an increased number of transporters causes greater activity of this process in the resistant cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015986405834
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 5
    Electronic Resource
    Electronic Resource
    Receptor-Mediated Transport of Peptide Hormones and Its Importance in the Overall Hormone Disposition in the Body (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 192-202 
    Details
    ISSN: 1573-904X
    Keywords: receptor-mediated endocytosis ; peptide hormones ; epidermal growth factor ; down-regulation ; silent receptor ; internalization ; liver perfusion method ; multiple indicator dilution method ; physiological pharmacokinetic model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A remarkable feature of the pharmacokinetics of polypeptide hormones is the contribution of specific binding sites (receptors) to the polypeptide hormone distribution and clearance in the body. The concept of “transport receptor” is now well established, and receptor-mediated endocytosis (RME) is recognized as a general mechanism in the uptake of biologically important peptide hormones. This article focuses on the kinetic analysis of the RME of polypeptides, based mainly upon the observations of the kinetics of epidermal growth factor in the liver. The following points are emphasized: (1) How can we determine the existence and the kinetic constants of polypeptide RME in vivo and in the perfused liver system? A liver perfusion method, the single-pass multiple-indicator dilution technique, has been shown to be suitable for analyzing the dynamics of interaction of peptide hormones with their cell surface receptors. (2) What is the importance of down-regulation of transport receptors to the overall kinetics of polypeptides in vivo? Time profiles of polypeptide plasma concentrations and their surface receptors in the liver after iv administration of epidermal growth factor were simulated with a physiologic pharmacokinetic model that includes kinetic constants representing the interaction of polypeptides and their receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015905331391
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 6
    Electronic Resource
    Electronic Resource
    Uptake of Colchicine, a Microtubular System Disrupting Agent, by Isolated Rat Hepatocytes (1989)
    Springer
    Pharmaceutical research 6 (1989), S. 235-238 
    Details
    ISSN: 1573-904X
    Keywords: colchicine ; hepatic uptake ; isolated hepatocyte ; microtubule
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The possible mechanism of hepatic uptake of colchicine (CLC), a microtubule system disrupting agent, was examined using isolated rat hepatocytes. The existence of a carrier-mediated active transport system for CLC was demonstrated. This transport system is saturable, is affected by metabolic inhibitors (dinitrophenol, KCN) and a SH-group blocker (p-hydroxymercuribenzoic acid but not N-ethylmaleimide), and is sensitive to temperature. Ouabain, an inhibitor of Na+, K+-ATPase, does not affect the transport system of CLC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015917601349
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 7
    Electronic Resource
    Electronic Resource
    Effect of albumin on hepatic uptake of warfarin in normal and analbuminemic mutant rats: Analysis by multiple indicator dilution method (1986)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 14 (1986), S. 51-64 
    Details
    ISSN: 1573-8744
    Keywords: hepatic uptake ; warfarin ; multiple indicator dilution method ; albumin-mediated transport ; analbuminemic rat (NAR)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Multiple indicator dilution studies of warfarin uptake were carried out on isolated perfused rat livers in the presence and absence of bovine serum albumin (BSA) in the perfusate using normal rats and Nagase analbuminemic rats (NAR). A distributed model was fitted to the dilution data and estimates of influx, efflux, and sequestration rate constants were obtained. In both groups of rats, the intrinsic clearance for unidirectional hepatic uptake (CLinl,influx) of warfarin in the presence of 1.6g/dl BSA was approximately 37–45% of that in the absence of BSA, while the unbound fraction of warfarin with 1.6 g/dl BSA in the perfusate was only 4.2% of that in the absence of BSA. Thus the degree of BSA-induced reduction of the value of CLinl,influx and that of the unbound fraction are different. From these observations, it was found that the hepatic uptake of warfarin is not driven solely by the unbound concentration of warfarin, supporting the recent concepts of albumin-mediated transport for tightly albumin bound ligands as reported by Ockner et al. In addition, the fact that the same hepatic uptake mechanism of warfarin was also observed in NAR suggested that the hepatic uptake of warfarin may not necessarily require a special albumin receptor on the hepatocyte surface.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059283
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 8
    Electronic Resource
    Electronic Resource
    Effect of a diffusional barrier to a metabolite across hepatocytes on its kinetics in “enzyme-distributed” models: A computer-aided simulation study (1987)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 15 (1987), S. 399-421 
    Details
    ISSN: 1573-8744
    Keywords: diffusional barrier ; hepatic extraction ; enzyme-distributed model ; metabolite kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effect of a diffusional barrier to a metabolite between the blood and hepatocytes on elimination kinetics of formed and preformed metabolites was predicted under various enzymic distributions in the liver by computer- aided simulation. Sequential metabolism by which the primary metabolite (MI) is generated from the parent drug (D) and further metabolized to the terminal metabolite (MII) by enzymes A and B, respectively, was chosen for the simulation. Moreover, four models of enzymic distribution patterns were defined with regard to the hepatic blood flow path. The extraction ratios for the preformed and formed metabolites (designated as Em and Ep→m, respectively) were simulated by varying both the average intrinsic clearance of enzyme B ( $$\overline {CL_{int,B} }$$ ) and the permeability of hepatocytes for MI ( $$\overline {P_m }$$ ), while keeping the average intrinsic clearance of enzyme A ( $$\overline {CL_{int,A} }$$ ) equal to hepatic blood flow (Q). When a rapid equilibrium of MI between the blood and hepatocytes held, i.e., $$\overline {P_m }$$ was large relative to Q, Em was equal to or higher than Ep→m for all models, as previously shown by Pang and Stillwell. By contrast, it was found that when a diffusional barrier for MI existed, i.e., $$\overline {P_m }$$ was small relative to Q, Em was equal to or lower than Ep→m. Furthermore, it was observed that the smaller $$\overline {P_m }$$ became, the larger the difference between Em and Ep→m became. We further simulated the effect of the intrinsic clearance ( $$\overline {CL_{int,C} }$$ ) for a metabolic pathway, which competes for that by enzyme A. on the E p→m value. In the model assuming even distribution of all the enzymes along the flow path, irrespective of the $$\overline {CL_{int,C} }$$ value, a similar effect of $$\overline {P_m }$$ on Ep→m was observed when the $$\overline {P_m }$$ value was relatively small ( $$\overline {P_m }〈 Q$$ ). By contrast, in the case of uneven enzymic distributions of enzymes A and B, the effect of the $$\overline {CL_{int,C} }$$ value on the relationship between Pm and Ep→m occurred to some extent. From these simulations, it was concluded that lower membrane permeability ( $$\overline {P_m }$$ ) both diminishes the entry of preformed metabolite into the hepatocytes and accelerates the removal of intracellularly formed metabolite (through sequential metabolism) by diminishing its efflux, yielding lower Em than Ep→m. When $$\overline {P_m }$$ becomes small ( $$\overline {P_m }〈 1/10Q$$ ), these mechanisms for lower Em than Ep→m predominate over other mechanisms such as the presence of a competing metabolic route and uneven distribution of enzymes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01066521
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 9
    Electronic Resource
    Electronic Resource
    Analysis of nonlinear tissue distribution of quinidine in rats by physiologically based pharmacokinetics (1985)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 13 (1985), S. 425-440 
    Details
    ISSN: 1573-8744
    Keywords: quinidine disposition ; tissue distribution ; nonlinear tissue binding ; physiological pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The nonlinear tissue distribution of quinidine in rats was investigated by a physiologically based pharmacokinetic model. Serum protein binding of quinidine showed a nonlinearity over thein vivo plasma concentration range. The blood-to-plasma concentration ratio (C b/C p) of quinidine also showed a concentration dependence. The steady-state volume of distribution (V ss) determined over the plasma concentration range from 0.5 to 10 μg/ml was 6.0 ±0.45 L/kg. The tissue-to-plasma partition coefficient (Kp) of muscle, skin, liver, lung, and gastrointestinal tract (GI) showed a nonlinearity over thein vivo plasma concentration range of quinidine, suggesting saturable tissue binding. The concentration of quinidine in several tissues and plasma was predicted by a physiologically based pharmacokinetic model usingin vitro plasma protein binding and theC b/C p of quinidine. The tissue binding parameters were estimated fromin vivo Kp values. The predicted concentration curves of quinidine in each tissue and in plasma showed good agreement with the observed values.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061478
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
  • 10
    Electronic Resource
    Electronic Resource
    Kinetic analysis of albumin-mediated uptake of warfarin by perfused rat liver (1988)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 16 (1988), S. 165-181 
    Details
    ISSN: 1573-8744
    Keywords: warfarin ; hepatic uptake ; hepatic clearance ; liver perfusion ; multiple indicator dilution method ; distributed model ; albumin-mediated transport ; difiusional clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We previously found that the uptake of warfarin in the presence of albumin by perfused rat liver could not be explained simply by the unbound warfarin concentration. The aim of the present study is to develop a kinetic model to account for this albumin- mediated uptake of warfarin. Single circulation indicator dilution studies on warfarin uptake were carried out in the isolated perfused rat liver in the absence and presence of various concentrations of bovine serum albumin (BSA) in the perfusate. A distributed model was fitted to the dilution data and the estimates of the influx, efflux, and sequestration rate constants were obtained. The results showed that the predicted concentration of the unbound warfarin is not high enough to explain the observed uptake rate; the liver cell surface appears to reduce the binding affinity of warfarin for BSA to 1/20 of that observed in vitro.A kinetic model which considers the interaction between albumin and the liver cell surface was fitted to the uptake rates of warfarin over a wide range of BSA concentration. The model gave a dissociation constant of the cell surface for albumin of 160 μM, which is comparable with those reported by others for the hepatic extractions of free fatty acids and rose bengal. Based on this kinetic model, the contributions of the unbound and bound warfarin to its hepatic uptake were estimated, and the bound warfarin was found to contribute most in the physiological albumin concentration range.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01062259
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...