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  • 1
    ISSN: 1573-904X
    Keywords: allometric scaling ; interspecies scaling ; pharmacokinetics ; clearance ; in vitro models ; bosentan
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The goal of this study was to find a rational and reliable method of using animal data to predict the clearance of metabolised drugs in humans. Methods. One such approach is to use in vitro liver models (e.g. hepatocytes and microsomes) to determine the relative capacities of the various animal species and humans to metabolise the test compound. These data can then be combined with the in vivo clearances in animals, to calculate the in vivo clearance in humans using allometric scaling techniques. In this study, this approach was evaluated with a new endothelin receptor antagonist, bosentan, which is eliminated mainly through metabolism and is characterized by very large interspecies differences in clearance. Therefore, this compound provided a stringent test of our new extrapolation method for allometric scaling. Results. The results obtained with bosentan showed that adjusting the in vivo clearance in the different animal species for the relative rates of metabolism in vitro gave a far better prediction of human clearance than an empirical correcting factor (brain weight). Conclusions. This approach provided a more rational basis for predicting the clearance of metabolised compounds in humans.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-904X
    Keywords: microdialysis ; protein binding ; equilibrium dialysis ; in vitro-in vivo binding
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The aim of the present study was to compare the performance of conventional equilibrium dialysis method with a microdialysis method in studying drug protein binding. The two methods were assessed by comparing the measured mean unbound drug fraction in different plasma species in vitro in plasma of four different species and at two concentrations of the non-indolic melatonin analog S 20098. For the microdialysis study, the unbound drug fraction was calculated after correction for membrane recovery. Plasma protein binding of S 20098 ranged from 75 to 95%. In humans, rabbits and rats (10 ng/ml), equal unbound percentages were found between equilibrium dialysis and microdialysis. Microdialysis gave slightly but significantly higher values in rat (2000 ng/ml), and in monkey plasma independent of the drug concentration. Microdialysis was also performed in vivo in freely moving rats under steady-state conditions, yielding similar unbound fraction values (26.0 ± 0.9%) to those obtained using microdialysis probes in rat plasma in vitro (24.4 ± 1.6%). These results support the use of in vivo microdialysis in pharmacokinetic studies in freely moving animals.
    Type of Medium: Electronic Resource
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