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 (approximately 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 approximately 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Riggs
K W
KW
Faculty of Pharmaceutical Sciences, Grace Hospital, Vancouver, British Columbia, Canada.
Rurak
D W
DW
Taylor
S M
SM
McErlane
B A
BA
McMorland
G H
GH
Axelson
J E
JE
D000818:Animals; D001785:Blood Gas Monitoring, Transcutaneous / Q000662:veterinary; D002404:Catheterization / Q000662:veterinary; D005260:Female; D005333:Fetus / Q000378:metabolism*; D007262:Infusions, Intravenous / Q000662:veterinary; D007275:Injections, Intravenous / Q000662:veterinary; D008431:Maternal-Fetal Exchange; D008657:Metabolic Clearance Rate; D008787:Metoclopramide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D012756:Sheep / Q000378:metabolism*
D008787:Metoclopramide