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.
Footnotes
-
Send reprint requests to: Dr. Peter W. Angus, Liver Transplantation Unit, Austin and Repatriation Medical Center, Heidelberg, Victoria 3084 Australia. E-mail: peter.angus{at}armc.org.au
-
This study was supported by the National Health and Medical Research Council and the Austin Hospital Medical Research Foundation.
- Abbreviations used are::
- RVF
- right ventricular failure
- PAC
- pulmonary artery constriction
- CYP
- cytochrome P450
- E
- steady-state hepatic extraction
- Cin
- inflow drug concentration
- Cout
- outflow drug concentration
- Q
- perfusate flow
- CLint
- intrinsic clearance
- IPRL
- isolated perfused rat liver
- Received October 21, 1999.
- Accepted July 6, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
DMD articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|