Conjugation of para-nitrophenol by the isolated perfused neonatal sheep liver.
We examined the metabolism of para-nitrophenol (PNP) in the isolated perfused neonatal sheep liver (n = 8, 0.25-11 days) and compared the findings with our previous data from the perfused near-term fetal sheep liver (Ring, J. A., et al. Drug Metab Dispos 1996, 24, 1378). A three-step dosage regimen was used (72, 144, and 288 micromol of PNP). At the end of each dosage phase, PNP had fallen below detectable levels, and 101 +/- 16% of the dose was accounted for as PNP conjugates. Elimination of PNP from perfusate varied with dose. Elimination was first order with the 72-micromol dose; with the 144-micromol dose, elimination was first order in four livers but Michaelis-Menten kinetics in the remaining four. With all the 288-micromol doses, elimination was Michaelis-Menten and gave the following biochemical parameters: K(m) = 255 +/- 138 microM (fetal = 14.7 microM, P < 0.01), V(max) = 515 +/- 285 nmol/min/g liver (fetal = 34.3 nmol/min/g liver, P < 0.01), and intrinsic hepatic clearance = 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 (range, 0.40-1.0) and strongly correlated with neonatal age (r = 0.90, P < 0.05). We conclude that PNP is highly extracted by the isolated perfused neonatal sheep liver at much higher efficiency than in the near-term fetal sheep, reflecting a maturation of conjugation that progresses further in the early neonatal period.
Gow
P J
PJ
Department of Medicine, Austin and Repatriation Medical Centre, West Heidelberg, Victoria 3081, Australia.
Ghabrial
H
H
Treepongkaruna
S
S
Shulkes
A
A
Smallwood
R A
RA
Morgan
D J
DJ
Ching
M S
MS
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001646:Bile / Q000502:physiology; D001659:Biliary Tract / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000196:embryology / Q000378:metabolism* / Q000502:physiology; D008297:Male; D009596:Nitrophenols / Q000378:metabolism* / Q000493:pharmacokinetics; D010477:Perfusion; D011247:Pregnancy
D009596:Nitrophenols; C024836:4-nitrophenol