Metoclopramide Pharmacokinetics in Pregnant and Nonpregnant Sheep

The pharmacokinetics of metoclopramide was studied in chronically instrumented pregnant and nonpregnant sheep. Metoclopramide was administered to the ewe by intravenous bolus injections (on a crossover basis) of 10, 20, and 40 mg, with an additional 80‐mg dose to the nonpregnant animals. Transfer of the drug to the fetus was rapid with significant concentrations in fetal plasma 1 min after maternal dosing. The ratio of fetal‐to‐maternal area under the plasma concentration–time curves averaged 0.74, indicating significant fetal exposure to the drug. Maternal metoclopramide administration resulted in minimal fetal effects, with no change in arterial pressure, heart rate, or arterial pH or Pco2, and only a small (∼ 1.8 mm Hg) transient decline in Po2. Plasma concentrations in maternal and fetal plasma in most animals were best described by a biexponential equation with rapid distribution and elimination phases. The terminal elimination half‐lives in maternal and fetal plasma averaged 71.3 and 86.8 min, respectively, with fetal half‐life being significantly longer. The number of fetuses present had no consistent effects on either maternal or fetal pharmacokinetic parameters. Total body clearance and volume of distribution averaged 3.5 L/h/kg and 5.8 L/kg, respectively, in the pregnant ewe, and 4.5 L/h/kg and 6.9 L/kg, respectively, in the nonpregnant animals. The terminal elimination half-life in the nonpregnant ewes averaged 67.5 min. Pharmacokinetic parameters were compared in the pregnant and nonpregnant ewes at the 10-, 20-, and 40-mg doses, and no significant differences were observed in the distribution or elimination rate constants, elimination half-life, or volume of distribution. Total body clearance in the nonpregnant animals, however, was 22% higher than that calculated in the pregnant animals. Metoclopramide was observed to follow linear or dose-independent kinetics in both the pregnant and nonpregnant ewe over the 4–8-fold dose range studied.