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  • 1
    Electronic Resource
    Electronic Resource
    A New Bleaching Protocol for Hyperpigmented Skin Lesions with a High Concentration of All-trans Retinoic Acid Aqueous Gel (1999)
    Springer
    Aesthetic plastic surgery 23 (1999), S. 285-291 
    Details
    ISSN: 1432-5241
    Keywords: Key words: Retinoic acid—Hydroquinone—Bleaching—Aqueous gel—Hyperpigmentation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. A new bleaching protocol for skin hyperpigmentation with a higher concentration of all-trans retinoic acid (atRA) aqueous gel than those commercially available is introduced. AtRA aqueous gel (0.1%) was applied topically twice a day along with 4% hydroquinone, 7% lactic acid ointment to oriental patients with hyperpigmented lesions such as senile lentigines, melasma, and postinflammatory hyperpigmentation. The clinical results of 39 patients treated with 0.1% atRA aqueous gel were compared to those of 22 patients treated with 0.1% atRA hydrophilic ointment. Better clinical results and subjective satisfaction were obtained through a significantly shorter period of treatment with 0.1% atRA aqueous gel than with 0.1% atRA hydrophilic ointment, although side effects such as erythema and irritation were seen at a higher frequency. It is suggested that our bleaching protocol with a high concentration of atRA aqueous gel in combination with hydroquinone and lactic acid has a strong bleaching ability and a potential as a standard therapy for various kinds of skin lesions with hyperpigmentation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002669900285
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  • 2
    Electronic Resource
    Electronic Resource
    Physiologically based pharmacokinetics of drug-drug interaction: A study of tolbutamide-sulfonamide interaction in rats (1982)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 10 (1982), S. 297-316 
    Details
    ISSN: 1573-8744
    Keywords: drug-drug interaction ; tolbutamide-sulfonamide interaction ; sulfaphenazole ; sulfadimethoxine ; sulfamethoxazole ; physiological pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A blood flow rate-limited pharmacokinetic model was developed to study the effect of sulfonamide on the plasma elimination and tissue distribution of14C -tolbutamide (TB) in rats. The sulfonamides (SA) used were sulfaphenazole (SP), sulfadimethoxine (SDM), and sulfamethoxazole (SMZ). The tissue-to-plasma partition coefficients (Kp) of all tissues studied, i.e., lung, liver, heart, kidney, spleen, G.I. tract, pancreas, brain, muscle, adipose tissue, and skin, increased in the presence of SA, but except for brain, liver, and spleen, the tissue-to-plasma unbound concentration ratio (Kp, f) of other tissues did not show a significant alteration. This suggested that the tissue binding of TB is not affected by SA and that the increase of Kp is due mainly to the displacement of plasma protein-bound TB by SA. The concentrations of TB in several tissues and plasma were predicted by a physiologically based pharmacokinetic model using in vitro plasma binding and metabolic parameters, the plasma-to-blood concentration ratio and the tissue-to-plasma unbound concentration ratios having been determined from both the tissue and plasma concentrations of TB at the β-phase after intravenous administration of TB and the plasma free fraction. The predicted concentration curves of TB in each tissue and in plasma showed good agreement with the observed values except for the brain, for which the predicted concentrations were lower than the observed values in the early time period. In the SP- and SDM-treated rats, the predicted free concentration of TB in the target organ, the pancreas, at 6 h was six times higher than that of the control rats. From these findings, it is suggested that physiologically based pharmacokinetic analysis could be generally useful to predict approximate plasma and tissue concentrations of a drug in the presence of drug-drug interaction.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059263
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  • 3
    Electronic Resource
    Electronic Resource
    Prediction of diazepam disposition in the rat and man by a physiologically based pharmacokinetic model (1983)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 11 (1983), S. 577-593 
    Details
    ISSN: 1573-8744
    Keywords: diazepam disposition ; physiological pharmacokinetics ; animal scale-up
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A physiologically based pharmacokinetic model for diazepam disposition was developed in the rat, incorporating anatomical, physiological, and biochemical parameters, i.e., tissue volume, blood flow rate, serum free fraction, distribution of diazepam into red blood cells, drug metabolism and tissue-to-blood distribution ratio. The serum free fraction of diazepam was determined by equilibrium dialysis at 37°C and was constant over a wide concentration range. Partition of diazepam between plasma and erythrocytes was determined in vitroat 37°C, and the resultant blood-to-plasma concentration ratio was constant over a wide concentration range. The enzymatic parameters (Km, Vmax)of the eliminating organs, i.e., liver, kidney, and lung, previously determined using microsomes, were used for the prediction. The tissue-to-blood distribution ratios inferred by inspection of the data when pseudoequilibrium is reached after i.v. bolus injection of 1.2 mg/kg diazepam were corrected according to the method of Chen and Gross. Predicted diazepam concentration time-course profiles in plasma and various organs or tissues, using an 11-compartmental model, were compared with those observed. Prediction was successful in all compartments including brain, the target organ of diazepam. Scale-up of the disposition kinetics of diazepam from rat to man was also successful.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01059058
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  • 4
    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
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  • 5
    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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  • 6
    Electronic Resource
    Electronic Resource
    Stereospecific Distribution of Methylphenidate Enantiomers in Rat Brain: Specific Binding to Dopamine Reuptake Sites (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 407-411 
    Details
    ISSN: 1573-904X
    Keywords: methylphenidate enantiomers ; intravenous administration ; brain striatum ; dopamine reuptake site ; stereospecific binding ; rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract To investigate the stereoselective distribution of methylphenidate (MPD) enantiomers in rats, the concentrations of each enantiomer were determined in plasma and brain regions (cerebellum, striatum, basal forebrain, brain stem, and cortex) after iv administration of racemic MPD and its individual enantiomers. The concentrations of MPD enantiomers in each brain region reached pseudo-steady state within 10 min after iv administration of racemic MPD (2 mg/kg dose). The influx clearances for MPD calculated from K Papp values in each brain region were not significantly different between MPD enantiomers and between the five brain regions. The mean K Papp values for (+ )-MPD in the striatum at 120 and 240 min after administration of racemic MPD were 10.1 and 10.5, respectively, and these values at each time were significantly larger than the K Papp values (7.5 and 7.0, respectively) for the (–)-isomer (P 〈 0.01). The K Papp value for (+ )-MPD in the striatum decreased by coadministration of mazindol as an inhibition of both dopamine and norepinephrine reuptake, but it was not changed by desipramine as a norepinephrine reuptake inhibitor. These results suggest that ( + )-MPD was bound specifically to the dopamine reuptake site in the striatum.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018917205292
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  • 7
    Electronic Resource
    Electronic Resource
    Comparison of the Hepatic Uptake Clearances of Fifteen Drugs with a Wide Range of Membrane Permeabilities in Isolated Rat Hepatocytes and Perfused Rat Livers (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 434-440 
    Details
    ISSN: 1573-904X
    Keywords: hepatic uptake clearance ; rat hepatocytes ; perfused rat liver ; unstirred water layer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The hepatic uptake clearances of 15 ligands with a wide range of permeabilities were determined in rats using two techniques: centrifugal filtration with isolated hepatocytes and the multiple indicator dilution (MID) method with isolated perfused livers. Some of the uptake clearance values were taken from the literature. Uptake clearance values obtained from isolated hepatocytes were extrapolated to that per gram liver (PS inf, cell), assuming that 1 g of liver has 1.3 × 108 cells. The values of PS inf, cell varied from approximately 0.1 to 72 (mL/min/g liver). The values of PS inf, cell were similar to those (PS inf,MID) determined by the MID method for ligands with uptake clearances below approximately 1 mL/min/g liver. However, for the ligands with larger uptake clearances, the PS inf, MID values were lower than the PS inf,cell values and appeared to reach an upper limit (approx. 15–20 mL/min/g liver). The PSinf,cell values of 1-propranolol, tetraphenylphosphonium (TPP+), and diazepam were 72, 43, and 22 mL/min/g liver, respectively, whereas their uptake clearances (PS inf,MID) determined by the MID method were 4 to 10 times lower. One of the possible mechanisms for this discrepancy is that an unstirred water layer, which may exist in Disse's space in isolated perfused livers (and probably under in vivo condition), limits the hepatic uptake rate of ligands with extremely high membrane permeabilities.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018952709120
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  • 8
    Electronic Resource
    Electronic Resource
    Effect of Renal or Hepatic Dysfunction on Neurotoxic Convulsion Induced by Ranitidine in Mice (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 1519-1523 
    Details
    ISSN: 1573-904X
    Keywords: ranitidine ; neurotoxicity ; renal dysfunction ; hepatic dysfunction ; H2 antagonists
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract We investigated the effect of acute renal and hepatic dysfunction on the neurotoxicity of ranitidine, a histamine H2 receptor antagonist. Experimental acute hepatic and renal dysfunction in mice were produced by i.p. injection of uranyl nitrate (UN) and carbon tetrachloride (CT), respectively. Ranitidine was then constantly infused into the tail vein until the onset of clonic convulsion. When compared to control mice, UN treated mice had a significantly shorter onset time to clonic convulsion, lower total dose and higher plasma concentration at initiation of clonic convulsion. In contrast, the convulsive threshold concentration in the brain of UN treated mice was not significantly different from that of control mice. In CT treated mice, all pharmacokinetic and pharmacodynamic data described above were not significantly different from those of the control mice. No significant difference in the brain/plasma concentration ratio was observed between both disease models and the corresponding control mice. Finally, the effect of UN and CT treatment on the convulsive potency after intracerebral (i.e.) administration of ranitidine was investigated in mice. Potentiation of the intrinsic neurotoxic sensitivity to ranitidine could not be demonstrated for mice with renal or hepatic dysfunction. From these findings, we conclude that renal dysfunction is a risk factor for ranitidine neurotoxicity, and this increased risk results from increase in the drug concentration in plasma and brain as a result of impaired renal excretion. No apparent effect of acute hepatic dysfunction was observed on both the pharmacokinetic and pharmacodynamic behavior of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018933031526
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  • 9
    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
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  • 10
    Electronic Resource
    Electronic Resource
    Classification of benzodiazepine hypnotics in humans based on receptor occupancy theory (1993)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 21 (1993), S. 31-41 
    Details
    ISSN: 1573-8744
    Keywords: benzodiazepine ; hypnotics ; receptor occupancy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Benzodiazepine (BZP) hypnotics are now classified into four groups according to their plasma elimination rates: ultrashort-, short-, intermediate-, and long-acting drugs. Since the specific binding affinities for the BZP receptor vary widely among the BZPs and their active metabolites, it may be more reasonable to correlate their pharmacological activities with the BZP receptor occupancy rather than with their plasma concentrations. The time courses of total plasma concentrations of BZPs and their active metabolites after a single oral administration were obtained from the literature, and their unbound concentrations (Cu)were calculated from the reported values of their plasma unbound fractions. The data of the receptor binding affinities of the BZPs, reported as dissociation constants (Kd)determined by in vitrobinding experiments, were also obtained from the literature. Using these values, the time courses of receptor occupancies [Cu/(Kd + Cu) ×100%] were calculated for the various BZPs. A mutual competitive inhibition was considered in the case of the drugs that had active metabolites. Although plasma total and unbound concentration time profiles of the BZPs showed a wide variation, similar patterns were obtained for the time courses of the receptor occupancy among the BZPs in each group, indicating that the BZP hypnotics can be classified more conveniently based on receptor occupancy theory.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01061774
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