Effects of Acute Moderate Hypoxemia on Kinetics of Metoclopramide and its Metabolites in Chronically Instrumented Sheep

Hypoxemia is known to induce various physiological changes which can result in alteration in drug pharmacokinetics. To examine the effect of acute moderate hypoxemia on metoclopramide (MCP) pharmacokinetics, a continuous 14-hour infusion of MCP during a normoxemic, hypoxemic and subsequent normoxemic period was conducted in eight adult sheep. Arterial blood and urine samples were collected to examine the effects on the pharmacokinetics of MCP and its deethylated metabolites. MCP and its mono- and di-deethylated metabolites were quantitated using a GC/MS method. Steady-state concentrations of MCP were achieved in each of the three periods. During hypoxemia, MCP plasma steady-state concentration increased significantly from 50.72$\pm$1.06 to 63.62$\pm$1.79 ng/mL, and later decreased to 55.83$\pm$1.15 ng/mL during the post-hypoxemic recovery period. Total body clearance ($CL_{TB}$) of MCP was significantly decreased from 274.2$\pm$48.0 L/h to 205.40$\pm$28.2 L/h during hypoxemia, and later restored to 245.8$\pm$44.2 L/h during the post-hypoxemic period. Plasma mono-deethylated MCP concentration (32.78$\pm$1.73 ng/mL) also increased, compared to the control group (21.20$\\pm$1.39 ng/mL), during hypoxemia and subsequent normoxemic period. Renal excretion of MCP and its metabolites was also decreased during hypoxemia, while urine flow was increased with a concomitant decrease in urine osmolality. Thus, the results indicate that acute moderate hypoxemia affects MCP pharmacokinetics.