title: Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation.
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.
authors.affiliation: Department of Medicine, University of Queensland, Princess Alexandra Hospital, Woollongabba, Queensland 4102, Australia.
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Hung
authors.forename: Gerhard A
authors.initials: GA
authors.lastname: Siebert
authors.forename: Ping
authors.initials: P
authors.lastname: Chang
authors.forename: Michael W
authors.initials: MW
authors.lastname: Whitehouse
authors.forename: Linda
authors.initials: L
authors.lastname: Fletcher
authors.forename: Darrell H G
authors.initials: DH
authors.lastname: Crawford
authors.forename: Michael S
authors.initials: MS
authors.lastname: Roberts
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000410:Alanine Transaminase / Q000097:blood; D000465:Algorithms; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D001219:Aspartate Aminotransferases / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D003627:Data Interpretation, Statistical; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D009961:Orosomucoid / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D011433:Propranolol / Q000493:pharmacokinetics*; D051381:Rats
chemical_list: D000319:Adrenergic beta-Antagonists; D009961:Orosomucoid; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol; D007501:Iron; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase