Neonatal Hepatic Propranolol Elimination: Studies in the Isolated Perfused Neonatal Sheep Liver

• Published in: Journal of pharmaceutical sciences Vol. 89; no. 5; pp. 586 - 593
• Main Authors: Gow, Paul J., Treepongkaruna, Saard, Ghabrial, Hany, Shulkes, Arthur, Smallwood, Richard A., Morgan, Denis J., Ching, Michael S.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York Elsevier Inc 01.05.2000; John Wiley & Sons, Inc; Wiley; American Pharmaceutical Association
• Subjects: Adrenergic beta-Antagonists - metabolism; Adrenergic beta-Antagonists - pharmacokinetics; Animals; Animals, Newborn; Biological and medical sciences; Catecholaminergic system; General pharmacology; In Vitro Techniques; Liver - metabolism; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Perfusion; Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions; Pharmacology. Drug treatments; Propranolol - metabolism; Propranolol - pharmacokinetics; Sheep; Animal model; Digestive system; Metabolite; Liver; Perfusion fluid; Metabolism; In vitro; β-Adrenergic receptor; Vertebrata; Mammalia; Newborn animal; Sheep; Artiodactyla; Antagonist; Pharmacokinetics; Propranolol; Ungulata; Bile; Beta blocking agent
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/(SICI)1520-6017(200005)89:5<586::AID-JPS4>3.0.CO;2-6

Using the isolated perfused neonatal sheep liver model, we examined the disposition 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 45min of dosage, perfusate propranolol levels had fallen by three orders of magnitude to be less than the limit of detection. Perfusate disappearance curves were monoexponential in six experiments and biexponential in two experiments. The mean shunt‐corrected hepatic extraction ratio was 0.92 ± 0.09, much greater than that seen in the fetal sheep liver (0.26 ± 0.13, P < 0.0001) but still less than values in the adult sheep (0.97). At the conclusion of the perfusion, 4‐hydroxypropranolol was the major metabolite present and 5‐hydroxypropranolol and N‐desisopropylpropranolol were minor metabolites. We conclude that the isolated perfused neonatal sheep liver is a useful model with which to study the maturation of neonatal hepatic drug oxidation. Our study shows that propranolol is rapidly eliminated by the neonatal liver to form several 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. © 2000 Wiley‐Liss Inc. and the American Pharmaceutical Association J Pharm Sci 89: 586–593, 2000