Impaired Elimination of Propranolol Due to Right Heart Failure: Drug Clearance in the Isolated Liver and Its Relationship to Intrinsic Metabolic Capacity
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 ther...
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Published in | Drug metabolism and disposition Vol. 28; no. 10; pp. 1217 - 1221 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.10.2000
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 |
ISSN: | 0090-9556 1521-009X |