CLEARANCE BY THE LIVER IN CIRRHOSIS .1. RELATIONSHIP BETWEEN PROPRANOLOL METABOLISM INVITRO AND ITS EXTRACTION BY THE PERFUSED LIVER IN THE RAT

To delineate the factors responsible for impaired clearance in cirrhosis, we examined propranolol disposition in rats with carbon tetrachloride-induced cirrhosis and compared it with that in control animals, rats treated with chlorpromazine (an inhibitor of propranolol metabolism) and rats with acute liver injury. We measured the extraction ratio of propranolol by the isolated perfused liver and related it to estimates of propranolol drug-metabolizing enzyme activity in homogenates of the same livers. In control animals, drug-metabolizing enzyme activity (measured as the ratio V(max)/K(m)) averaged 5,319 +/- 1,193 ml/min; the extraction ratio in the perfused liver was close to 1.0 (0.97 +/- 0.01). Important decreases of microsomal enzyme activity were observed in rats treated with chlorpromazine (30 +/- 2 7 ml/min, p < 0.00 1) and in rats with acute liver injury (724 +/- 401 ml/min, p < 0.001), accounting for the decrease in the hepatic extraction ratio by the perfused liver (0.33 +/- 0.09 and 0.71 +/- 0.04, respectively, p < 0.01). In cirrhotic livers, enzyme activity was not significantly different from that of controls (3,592 +/- 1,857 ml/min) and could not account for the observed decrease in extraction (0.66 +/- 0.14, p < 0.01). The extraction of antipyrine by the isolated perfused liver was also measured as an index of microsomal enzyme activity and related to propranolol extraction. Antipyrine extraction was decreased by 90% in acute liver injury, compared with 33% in cirrhosis, suggesting a much greater reduction of microsomal enzyme activity in the former group, Despite these differences, the extraction ratio of propranolol was reduced to a similar extent in rats with cirrhosis (0.64 +/- 0.20) and in rats with acute liver injury (0.77 +/- 0.10) compared with controls (0.97 +/-0.02). These results suggest that factors other than decreased enzyme activity (i.e., impaired uptake) contribute to lower propranolol extraction in cirrhosis.