Conjugation of para-nitrophenol by the isolated perfused neonatal sheep liver

We examined the metabolism of para-nitrophenol (PNP) in the isolated perfus ed neonatal sheep liver (n = 8, 0.25-11 days) and compared the findings wit h our previous data from the perfused near-term fetal sheep liver (Ring, J. 8., et al. Drug Metab Dispos 1996, 24, 1378). A three-step dosage regimen was used (72, 144, and 288 mu mol of PNP). At the end of each dosage phase, PNP had fallen below detectable levels, and 101 +/- 16% of the dose was ac counted for as PNP conjugates,Elimination of PNP from perfusate varied with dose. Elimination was first order with the 72-mu mol dose; with the 144-mu mol dose, elimination was first order in four livers but Michaelis-Menten kinetics in the remaining four. With all the 288-mu mol doses, elimination was Michaelis-Menten and gave the following biochemical parameters: K-m = 2 55 +/- 138 mu M (fetal = 14.7 mu M, P < 0.01), V-max = 515 +/- 285 nmol/min /g liver (fetal = 34.3 nmol/min/g liver, P < 0.01), and intrinsic hepatic c learance = 2.36 +/- 1.21 mL/min/g liver (fetal = 4.74 mL/min/g liver, P > 0 .05). The mean shunt-corrected hepatic extraction ratio of PNP was 0.82 (ra nge, 0.40-1.0) and strongly correlated with neonatal age (r = 0.90, P < 0.0 5). We conclude that PNP is highly:extracted by the isolated perfused neona tal sheep liver at much higher efficiency than in the near-term fetal sheep , reflecting a maturation of conjugation that progresses further in the ear ly neonatal period. (C) 2000 Wiley-Liss, Inc. and the American Pharmaceutic al Association.