A comparison of morphine and methadone disposition in the maternal-fetal unit

The extent of fetal exposure to a drug is a function of placental and fetal clearances of the drug. We have compared the placental and fetal clearances of morphine and methadone under steady-state conditions in the chronic pregnant ewe preparation. Morphine and methadone were infused at constant rates to the mother and fetus, and steady-state maternal and fetal plasma concentrations of the drugs were determined by radioimmunoassay. At steady state after maternal infusion of the drugs, the maternal: fetal free drug concentration ratios were 7.6 +/- 0.6 for morphine and 2.9 +/- 0.6 for methadone. The clearance of morphine from mother to fetus (24.9 +/- 3.0 ml/min) was fifteenfold less than that of methadone (390.3 +/- 92.8 ml/min). Fetal nonplacental clearance of methadone (381 +/- 89.1 ml/min) was higher than that of morphine (125.6 +/- 15.3 ml/min). Fetal clearance accounted for 67.4 +/- 3.9% of total morphine clearance from the fetal compartment, but only 42.8 +/- 4.9% of total methadone clearance. Fetal clearance of methadone increases with age in the early third trimester. The lower extent of fetal exposure to morphine compared to methadone is due primarily to a slower clearance of morphine across the placenta from mother to fetus rather than a more rapid clearance of morphine by the fetus.