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

Hung, Daniel Y., Siebert, Gerhard A., Chang, Ping, Whitehouse, Michael W., Fletcher, Linda, Crawford, Darrell H. G. and Roberts, Michael S. (2006) Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation. American Journal of Physiology-gastrointestinal And Liver Physiology, 290 2: G343-G351. doi:10.1152/ajpgi.00155.2005

Author Hung, Daniel Y.
Siebert, Gerhard A.
Chang, Ping
Whitehouse, Michael W.
Fletcher, Linda
Crawford, Darrell H. G.
Roberts, Michael S.
Title Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation
Journal name American Journal of Physiology-gastrointestinal And Liver Physiology   Check publisher's open access policy
ISSN 0193-1857
Publication date 2006
Sub-type Article (original research)
DOI 10.1152/ajpgi.00155.2005
Volume 290
Issue 2
Start page G343
End page G351
Total pages 9
Editor M. Montrose
B. B. Rauner
Place of publication USA
Publisher American Physiological Society
Collection year 2006
Language eng
Subject C1
320602 Cell Physiology
730118 Organs, diseases and abnormal conditions not elsewhere classified
11 Medical and Health Sciences
1116 Medical Physiology
Abstract 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.
Keyword Gastroenterology & Hepatology
Acidic Vesicles
Iron Overload
Ion Trapping
Induced Arthritic Rats
Alpha(1)-acid Glycoprotein
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2007 Higher Education Research Data Collection
School of Medicine Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 15 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 17 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 15 Aug 2007, 09:59:17 EST