Neonatal hepatic propranolol elimination: Studies in the isolated perfusedneonatal sheep liver

Using the isolated perfused neonatal sheep liver model, we examined the dis position of propranolol(n = 8, age 0.25-10 days) and compared our findings with our previous study from the perfused near-term fetal sheep liver (Ring JA, et al. 1995. Drug Metab Dispos 23:190-196). Within 45 min of dosage, p erfusate propranolol levels had fallen by three orders of magnitude to be l ess than the limit of detection. Perfusate disappearance curves were monoex ponential in six experiments and biexponential in two experiments. The mean shunt-corrected hepatic extraction ratio was 0.92 +/- 0.09, much greater t han that seen in the fetal sheep liver (0.26 +/- 0.13, P < 0.0001) but stil l less than values in the adult sheep (0.97). At the conclusion of the perf usion, 4-hydroxypropranolol was the major metabolite present and 5-hydroxyp ropranolol and N-desisopropylpropranolol were minor metabolites. We conclud e that the isolated perfused neonatal sheep liver is a useful model with wh ich to study the maturation of neonatal hepatic drug oxidation. Our study s hows that propranolol is rapidly eliminated by the neonatal liver to form s everal metabolites at rates far greater than in the fetal liver, but rates of elimination have not yet reached that reported in the adult sheep liver. (C) 2000 Wiley-Liss Inc.