RT Journal Article SR Electronic T1 Conjugation of para-nitrophenol by isolated perfused fetal sheep liver. JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 1378 OP 1384 VO 24 IS 12 A1 J A Ring A1 H Ghabrial A1 M S Ching A1 A Shulkes A1 R A Smallwood A1 D J Morgan YR 1996 UL http://dmd.aspetjournals.org/content/24/12/1378.abstract AB Using our recently described, isolated perfused fetal sheep liver model, we have studied the metabolism and disposition of para-nitrophenol (PNP) in intact fetal liver. Fetal sheep (mean gestational age, 137 +/- 7 days; range, 127-145 days; n = 8) were delivered under anesthesia near term, and the livers were isolated and perfused in situ, via the umbilical vein, in an oxygenated 1-liter recirculating system, at pH 7.40 at 37 degrees C. The perfusate delivery rate was 4.39 +/- 1.46 ml/g liver/min. Either a 14-micromol (n = 4), 72-micromol (n = 3), or 144-micromol (n = 5) bolus dose of PNP was added to the reservoir. Samples were taken from the reservoir every 5-10 min, and all bile was collected at 15-30-min intervals. Elimination of PNP from perfusate demonstrated Michaelis-Menten kinetics, and the calculated pharmacokinetic parameters for PNP elimination were KM = 13.0 +/- 9.66 microM, Vmax = 32.1 +/- 22.4 nmol/min/g liver, and intrinsic clearance = 3.39 +/- 2.54 ml/min/g liver. At the end of the 120-min perfusion period, PNP could be accounted for entirely as PNP-sulfate (PNP-S) and PNP-glucuronide (PNP-G). The perfusate ratio of PNP-S to PNP-G at 120 min was 2.21 +/- 0.88 at the 14-micromol dose, 0.86 +/- 0.56 at the 72-micromol dose, and 0.31 +/- 0.17 at the 144-micromol dose, because of saturation of sulfate production with increasing dose. PNP-S and PNP-G were eliminated into bile in small amounts (<3% of dose), and the PNP-S/PNP-G ratio in bile was 1. We conclude that near-term fetal sheep liver can metabolize PNP to PNP-G and PNP-S with efficiencies that may be comparable to those of adults, that, as in adults, sulfation is of low capacity, relative to glucuronidation, and that, unlike adults, fetuses have little capacity to transport the PNP-G formed in the hepatocytes into bile.