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dc.contributor.authorHung, DY
dc.contributor.authorSiebert, GA
dc.contributor.authorChang, P
dc.contributor.authorAnissimov, YG
dc.contributor.authorRoberts, MS
dc.date.accessioned2007-07-13
dc.date.accessioned2017-03-01T20:29:52Z
dc.date.available2017-03-01T20:29:52Z
dc.date.issued2004
dc.date.modified2009-03-02T02:57:14Z
dc.identifier.issn0022-3565
dc.identifier.doihttp://dx.doi.org/10.1124/jpet.104.070011
dc.identifier.urihttp://hdl.handle.net/10072/21557.1
dc.description.abstractThe 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.
dc.description.peerreviewedYes
dc.description.publicationstatusYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics
dc.publisher.placeUnited States
dc.relation.ispartofpagefrom822
dc.relation.ispartofpageto829
dc.relation.ispartofissue2
dc.relation.ispartofjournalThe Journal of Pharmacology and Experimental Therapeutics
dc.relation.ispartofvolume311
dc.subject.fieldofresearchPharmacology and pharmaceutical sciences
dc.subject.fieldofresearchcode3214
dc.titleDisposition Kinetics of Propranolol Isomers in the Perfused Rat Liver
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codec1x
gro.facultyFaculty of Science
gro.date.issued2004
gro.hasfulltextNo Full Text
gro.griffith.authorSiebert, Gerhard
gro.griffith.authorAnissimov, Yuri G.


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