Speaker
Description
Background: Propranolol is a widely used beta-blocker that exhibits rapid oral absorption, high hepatic extraction, and extensive tissue distribution. Although its absorption and disposition kinetics have been well-documented, interspecies similarities and differences have not been systematically assessed within a unified translational framework. This study aimed to characterize the pharmacokinetics (PKs) of propranolol across mammalian species and to develop a cross-species modeling approach to support human translation.
Methods: PK datasets for seven mammalian species (mouse, rat, rabbit, cat, dog, horse, and human) were compiled from the literature. Empirical allometric scaling was performed for clearance ($CL$) and steady-state volume of distribution ($V_{SS}$). A minimal physiologically-based pharmacokinetic (mPBPK) model was applied, with simultaneous fitting across species to estimate common distribution parameters, followed by species-specific fitting to characterize absorption and disposition kinetics. Model-based analyses were conducted using ADAPT 5.
Results: Allometric scaling demonstrated strong log-log linear relationships for $CL$ ($R^{2}=0.80$) and $V_{SS}$ ($R^{2}=0.98$) with body weight, although deviations were observed in rabbits and mice. Simultaneous fitting revealed largely conserved distribution kinetics ($f_{d1}≈0.95$ and $K_{P}≈1.18$). Model-based $CL$ values were generally consistent with non-compartmental analysis, whereas oral bioavailability varied substantially across species (e.g., 13% in rats and 45% in cats). Model-based in vivo estimates were compared with in vitro physicochemical properties to assess agreement in key PK parameters.
Conclusions: This cross-species mPBPK analysis suggests that propranolol disposition kinetics are largely conserved across mammals, while interspecies differences were observed in oral absorption and bioavailability.
