FETAL HEPATIC PROPRANOLOL METABOLISM - STUDIES IN THE ISOLATED-PERFUSED FETAL SHEEP LIVER

We have used an isolated perfused fetal sheep liver preparation to stu dy the fetal hepatic metabolism of propranolol in vitro in the intact organ. Eight livers were perfused in situ via the umbilical vein in an oxygenated recirculating system at 300 ml/min. Radiolabeled 15-mu m m icrospheres were used to quantify the hepatic ductus venosus shunt. Pr opranolol (4 mg) was dosed into the reservoir as a single bolus and pe rfusate and bile sampled over 150 min. Propranolol, 4-hydroxy proprano lol (40HP), 5-hydroxy propranolol (50HP), desisopropylpropranolol (DIP ), naphthoxylactic acid (NLA), and alpha-naphthoxyacetic acid (NAA) we re assayed by HPLC, before and after deconjugation by enzyme hydrolysi s. Mean age was 125 +/- 10 days, and mean liver weight was 66.1 +/- 18 .8 g. Oxygen consumption (1.10 +/- 1.03 mu mol/g/min), bile flow (0.51 +/- 0.18 mu l/g/min min), and perfusion pressure (8.7 +/- 3.3 mm Hg) were stable. Ductus venosus shunt was 41.6 +/- 17.4% of umbilical vein flow. Propranolol clearance was 26.2 +/- 13.4 ml/min, and shunt-corre cted extraction of propranolol was 0.26 +/- 0.13. The relative amounts of metabolites in perfusate after 150 min were: 40HP (25.1%), 50HP (5 .08%) (ring-oxidation products), DIP (6.57%), and NLA (4.33%) (side-ch ain oxidation products). No alpha NAA (a product of N-dealkylation of NLA) was detected. Except for NLA, metabolites were present predominan tly as conjugates. Biliary excretion of unchanged drug and metabolites accounted for a further 1.33% of the propranolol dose. These data ind icate that, although the hepatic clearance and extraction of propranol ol are low, the fetal sheep liver can metabolize propranolol by both r ing- and side-chain oxidation reactions and can conjugate these metabo lites.