title: Impaired elimination of propranolol due to right heart failure: drug clearance in the isolated liver and its relationship to intrinsic metabolic capacity.
abstract: It is unclear if reduced hepatic drug elimination in congestive heart failure is primarily due to impairment of enzyme function as a result of tissue hypoxia, to the direct effects of hepatic congestion, or to changes intrinsic to the liver, such as reductions in enzyme content and activity. We therefore compared propranolol clearance in perfused rat livers from animals with right ventricular failure (RVF) with that from control animals. Despite the fact that both groups were perfused at comparable flow rates, perfusion pressures, and levels of oxygen delivery, hepatic extraction of propranolol was significantly reduced in RVF livers (0.688 +/- 0.122 versus 0.991 +/- 0.006 ml/min/g of liver in controls, P <.001). This effect was reflected in a 97% reduction in propranolol intrinsic clearance in RVF livers (5 +/- 4 versus 172 +/- 82 ml/min/g of liver in controls, P <.01). In RVF livers, total hepatic CYP expression was reduced by 19% compared with controls, whereas cytochrome P450 isoenzymes 1A1/2 and 2D1 were reduced by 41 and 26%, respectively. Despite the 97% reduction in propranolol intrinsic clearance in perfused RVF liver, intrinsic clearance in microsomal preparations from the same livers was reduced by only 48% compared with controls (P <.05). These findings suggest that impaired propranolol clearance in RVF is not primarily accounted for by reduced hepatic oxygen delivery or by changes in hepatic content and activity of drug-metabolizing enzymes.
authors.affiliation: University of Melbourne, Department of Medicine, Austin and Repatriation Medical Center, Victoria, Australia.
authors.forename: C Y
authors.initials: CY
authors.lastname: Ng
authors.forename: H
authors.initials: H
authors.lastname: Ghabrial
authors.forename: D J
authors.initials: DJ
authors.lastname: Morgan
authors.forename: M S
authors.initials: MS
authors.lastname: Ching
authors.forename: R A
authors.initials: RA
authors.lastname: Smallwood
authors.forename: P W
authors.initials: PW
authors.lastname: Angus
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003250:Constriction; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism; D011433:Propranolol / Q000378:metabolism / Q000493:pharmacokinetics*; D011651:Pulmonary Artery / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D007527:Isoenzymes; D014665:Vasodilator Agents; D003577:Cytochrome P-450 Enzyme System; D011433:Propranolol