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Metoclopramide kinetics in sheep : maternal-fetal disposition, fetal pharmacodynamics and a comparison between pregnant and nonpregnant ewes Riggs, Kenneth Wayne


Metoclopramide (MCP) is a potent antiemetic and gastric motility modifier, widely used to treat nausea and vomiting and to promote gastric emptying. This thesis reports the modification of a previously developed capillary column electron-capture detection gas-liquid chromatographic assay for MCP and its application to the study of MCP pharmacokinetics in nonpregnant ewes, pregnant ewes and fetal sheep. A switch from the split to splitless mode of sample injection allows sample injection to be automated and increases sensitivity, with a lower limit of 2 ng/mL. Metoclopramide was administered to nonpregnant and pregnant ewes by intravenous (i.v.) bolus injections on a cross-over basis. Transfer of the drug to the fetus was rapid and the ratio of fetal to maternal area under the plasma concentration-time curves averaged 0.74 indicating significant fetal exposure. Plasma concentrations in maternal and fetal plasma were best described by a biexponential equation in most animals with rapid distribution and elimination phases. The terminal elimination half-lives in maternal and fetal plasma averaged 71.3 and 86.8 min, respectively. Total body clearance and volume of distribution averaged 3.5 L/h/kg and 5.8 L/kg in the pregnant ewes, and 4.7 L/h/kg and 7.2 L/kg in nonpregnant animals. The only significant difference in pharmacokinetic parameters was total body clearance, which was 24% higher in nonpregnant animals. MCP followed dose-independent kinetics in both the pregnant and nonpregnant ewe over the 4-8-fold dose range studied. The placental and nonplacental clearances of MCP were studied in pregnant sheep using a two compartment open model. MCP was administered to the ewe and fetus as an initial i.v. bolus followed by constant rate infusion to steady-state. The paired infusions were separated by 48-72 hours. A mean fetal to maternal steady-state concentration ratio of 0.57 was obtained following maternal drug administration. Protein binding of MCP at steady-state in maternal and fetal plasma averaged 49.5% and 39.5%. Total clearance of metoclopramide from the fetal lamb averaged 7.9 L/h/kg and was significantly greater than that in the ewe, 2.9 L/h/kg. Similarly, the placental clearance of drug from the fetus to the ewe (6.2 L/h/kg) was significantly greater than that from the maternal to the fetal compartment, 4.3 L/h/kg. Nonplacental clearance of MCP from the fetal compartment (1.7 L/h/kg) accounts for 20.5% of total fetal clearance, while nonplacental clearance from the maternal compartment (2.8 L/h/kg) contributes to 95.8% of the total clearance from the ewe. A marked accumulation MCP in fetal tracheal fluid occurred following both maternal and fetal dosing, with tracheal fluid concentrations exceeding those in fetal plasma by ≈15-fold. Significant accumulation also occurred in amniotic fluid. MCP persisted in both tracheal and amniotic fluids for more than 28 hours. Recirculation of MCP via fetal swallowing of these fluids as well as diffusion across fetal membranes may, in part, explain the longer half-life of MCP in fetal plasma. Transfer of MCP from the amniotic cavity was rapid, with significant concentrations in umbilical venous (UV) and fetal arterial (FA) plasma 5 min after intra-amniotic drug injection. MCP was not detected in maternal plasma for a further 5-15 min and concentrations were ≈13% of those in fetal plasma. MCP concentration in tracheal fluid again exceeded fetal plasma levels by 15-fold. MCP concentrations were higher in UV than FA plasma suggesting uptake of drug from the amniotic fluid by the chorioallantoic membranes. Amniotic fluid would appear to serve as a reservoir for the fetus, with drug entering the fetal circulation via fetal swallowing and diffusion across the chorioallantois. Maternal or fetal drug administration had no effect on fetal cardiovascular parameters and, except for a small (≈1.8 mm Hg), transient decline in PO₂ following maternal bolus dosing, fetal blood gases were unaltered. Amniotic pressure, breathing-like and electrocortical activities were also unaffected.

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