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 failu re is primarily due to impairment of enzyme function as a result of tissue hypoxia, to the direct effects of hepatic congestion, or to changes intrins ic to the liver, such as reductions in enzyme content and activity. We ther efore compared propranolol clearance in perfused rat livers from animals wi th 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 propranolo l 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, wh ereas 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). T hese findings suggest that impaired propranolol clearance in RVF is not pri marily accounted for by reduced hepatic oxygen delivery or by changes in he patic content and activity of drug-metabolizing enzymes.