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  • Disposition Kinetics of Propranolol Isomers in the Perfused Rat Liver

    Author(s)
    Hung, DY
    Siebert, GA
    Chang, P
    Anissimov, YG
    Roberts, MS
    Griffith University Author(s)
    Siebert, Gerhard
    Anissimov, Yuri G.
    Year published
    2004
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    Abstract
    The aim of this study was to define the determinants of the linear hepatic disposition kinetics of propranolol optical isomers using a perfused rat liver. Monensin was used to abolish the lysosomal proton gradient to allow an estimation of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were used for independent estimates of microsomal binding and intrinsic clearance. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a physiologically based pharmacokinetic model. Modeling showed an approximate ...
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    The aim of this study was to define the determinants of the linear hepatic disposition kinetics of propranolol optical isomers using a perfused rat liver. Monensin was used to abolish the lysosomal proton gradient to allow an estimation of propranolol ion trapping by hepatic acidic vesicles. In vitro studies were used for independent estimates of microsomal binding and intrinsic clearance. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a physiologically based pharmacokinetic model. Modeling showed an approximate 34-fold decrease in ion trapping following monensin treatment. The observed model-derived ion trapping was similar to estimated theoretical values. No differences in ion-trapping values was found between R(+)- and S(-)-propranolol. Hepatic propranolol extraction was sensitive to changes in liver perfusate flow, permeability-surface area product, and intrinsic clearance. Ion trapping, microsomal and nonspecific binding, and distribution of unbound propranolol accounted for 47.4, 47.1, and 5.5% of the sequestration of propranolol in the liver, respectively. It is concluded that the physiologically more active S()-propranolol differs from the R(+)-isomer in higher permeability-surface area product, intrinsic clearance, and intracellular binding site values.
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    Journal Title
    The Journal of Pharmacology and Experimental Therapeutics
    Volume
    311
    Issue
    2
    DOI
    https://doi.org/10.1124/jpet.104.070011
    Subject
    Pharmacology and Pharmaceutical Sciences
    Publication URI
    http://hdl.handle.net/10072/21557.1
    Collection
    • Journal articles

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