Accumulation and clearance of morphine-3-beta-D-glucuronide in fetal lambs.

The time course and extent of morphine-3-beta-D-glucuronide (M3G) production from morphine (MOR) and the clearance of M3G from plasma was studied in the late gestation fetal lamb. MOR was infused at a constant rate into the fetal vena cava and plasma was sampled from the fetus and ewe. Amniotic fluid was also sampled in one animal. M3G was produced in the fetal lamb and accumulated extensively in fetal plasma and amniotic fluid. Seizure activity was observed in two fetal lambs with extremely high plasma concentrations of M3G and MOR. The molar ratio of M3G to MOR in fetal plasma was dependent upon the duration of infusion, reaching a plateau of 60 at about 3 days, but appeared to be independent of the infusion rate over the range studied, 3 to 30 mg hr-1. Maternal plasma MOR and M3G concentrations were substantially less than corresponding fetal plasma concentrations. Using the steady-state plasma concentration of M3G obtained from infusion of MOR and the clearance of M3G derived from single injection of M3G to fetal lambs, the fraction of MOR converted to M3G by the fetus was calculated to be 0.63. Although MOR is conjugated to glucuronic acid in the fetal lamb and excreted into the amniotic fluid it is not readily transferred across the epitheliochorial placenta to the ewe because of restricted permeability.