Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in the mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a non-parametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher ₁-acid glycoprotein (orosomucoid) and iron tissue concentrations, but lower cytochrome P450 content. The hepatic extraction, metabolism and ion-trapping of propranolol were significantly impaired in the adjuvant-treated rats and could be correlated with altered iron store and cytochrome P450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology, biochemistry and consequently influences hepatic disposition of propranolol.