Distribution and fate of acetaminophen conjugates in fetal lambs in utero

The disposition of the two major metabolites of acetaminophen, acetaminophen glucuronide (A-G) and acetaminophen sulfate (A-S), was studied in nine chronically catheterized fetal lambs during the third trimester. After a bolus i.v. injection, both conjugates exhibited biphasic log plasma concentration vs. time curves with terminal half-lives of 3.36 to 7.60 hr for A-G and 4.61 to 8.20 hr for A-S. The steady-state volumes of distribution and the total clearances of both conjugates increased with the gestational age of the fetus. The ratios of renal clearance to total clearance were 1.00 +/- 0.06 and 0.95 +/- 0.07, respectively, for A-G and A-S. Neither placental transfer nor systemic hydrolysis of either conjugate was detectable in our experiments. The ratios of renal clearance to glomerular filtration rate, as determined by [14C] inulin renal clearance, were 0.96 +/- 0.06 and 0.67 +/- 0.10 for A-G and A-S, respectively. These ratios corresponded to the free fractions of the two conjugates in the plasma, which were 0.96 +/- 0.03 and 0.64 +/- 0.09, respectively, for A-G and A-S. Our data indicate that transplacental transfer of acetaminophen conjugates is not detectable and both conjugates are predominantly eliminated from the fetal plasma through renal excretion by glomerular filtration in the fetal kidney. As the conjugates are apparently not hydrolyzed in the fetus, they remain in the fetus and the surrounding amniotic fluid until birth.