The effect of input rate on the plasma disposition of propranolol enantiomers in the dog.

Drugs that exhibit nonlinear metabolism and a first-pass effect have bioavailabilities that are input rate dependent. In addition, if the metabolism of the individual isomers of a chiral compound is stereoselective then the plasma level ratio of the isomers, when dosed as a racemate may be input rate dependent. Since the therapeutic activity may reside in only one isomer the efficacy of an oral controlled release product may be dose rate dependent. In this document a physiological pharmacokinetic model is applied to the gastrointestinal tract, portal/liver system and plasma to describe the pharmacokinetics of (+)- and $(-)$-propranolol in dogs. The model parameters were obtained from IV and PO dosage form studies in four beagle dogs using a stereospecific assay for propranolol. The predicted change in dosage form of known release rate were well described by the model. The model can be applied to human pharmacokinetics in order to design more effective oral controlled release dosage forms.Ph.D.Health and Environmental SciencesPharmaceutical sciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128534/2/9023627.pd