Fetal and maternal placental and nonplacental clearances of metoclopramide in chronically instrumented pregnant sheep

The placental and nonplacental clearances of metoclopramide were studied in nine chronically instrumented, near-term pregnant sheep using a two-compartment open model. Metoclopramide was administered to the ewe and fetus on separate occasions as an initial iv bolus loading dose followed by a constant-rate infusion, with steady-state maternal and fetal plasma concentrations being obtained by 45 min. Following the maternal infusions, metoclopramide reached average steady-state concentrations of 50.0 ± 20.2 ng/mL in the ewe and 27.1 ± 8.6 ng/mL in the fetus, with a mean fetal-to-maternal concentration ratio of 0.57 ± 0.14. The ability of the fetus to eliminate metoclopramide by nonplacental routes appears to be responsible for this ratio being less than unity, rather than differential protein binding and ion-trapping effects. Mean steady-state concentrations were 13.8 ± 4.5 and 253.7 ± 92.1 ng/mL in the ewe and fetus, respectively, after fetal drug administration. Metoclopramide was bound significantly less to fetal (39.5 ± 8.9%) than to maternal (49.5 ± 7.9%) plasma proteins, with values similar to that reported for humans (≈ 40%). Clearance of metoclopramide across the placenta from the fetus to the ewe (6.2 ± 2.4 L/h/kg) was significantly greater than that in the reverse direction (4.3 ± 1.3 L/h/kg) and accounted for ≈ 80% of total fetal drug elimination. This may be explained by the higher percentage of fetal cardiac output to the placenta and the flow-limited transfer of this compound. Nonplacental routes (e.g., renal, hepatic) were responsible for only ≈ 20% of total fetal drug elimination (7.9 ± 2.9 L/h/kg), but, they comprised the major source (≈ 95%) of total maternal drug clearance (2.9 ± 0.4 L/h/kg). Neither maternal nor fetal drug administration resulted in any consistent or significant cardiorespiratory or behavioral effects in the fetal lamb, even though very high concentrations were obtained in fetal plasma following fetal dosing.