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Am J Physiol Gastrointest Liver Physiol 290: G343-G351, 2006. First published September 15, 2005; doi:10.1152/ajpgi.00155.2005
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INFLAMMATION/IMMUNITY/MEDIATORS

Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation

Daniel Y. Hung,1 Gerhard A. Siebert,1 Ping Chang,1 Michael W. Whitehouse,1 Linda Fletcher,2 Darrell H. G. Crawford,2 and Michael S. Roberts1

1Department of Medicine, University of Queensland, and 2Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Woolloongabba, Queensland, Australia

Submitted 1 April 2005 ; accepted in final form 8 September 2005

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 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 nonparametric 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 P-450 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 {alpha}1-acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.

acidic vesicles; iron overload; ion trapping


Address for reprint requests and other correspondence: M. S. Roberts, Dept. of Medicine, Univ. of Queensland, Princess Alexandra Hospital, Woollongabba, Queensland 4102, Australia (e-mail: m.roberts{at}uq.edu.au)






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