Disposition Kinetics of Propranolol Isomers in the Perfused Rat Liver
| Autor: | Ping Chang, Michael S. Roberts, Daniel Y. Hung, Gerhard A. Siebert, Yuri German Anissimov |
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| Přispěvatelé: | Roberts, Michael Stephen, Hung, D, Siebert, Gerhard, Chang, Ping, Anissimov, Yuri |
| Rok vydání: | 2004 |
| Předmět: |
Male
Kinetics Propranolol In Vitro Techniques Pharmacology monensin chemistry.chemical_compound First pass effect Isomerism Pharmacokinetics medicine Animals propranolol Rats Wistar Binding site Electrochemical gradient optical enantiomer Chromatography Chemistry Monensin Pharmacology and Pharmaceutical Sciences Rats ion-trapping Perfusion hepatic drug distribution Liver stereo-selectivity Microsome Molecular Medicine medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 311:822-829 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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