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Effects of acute moderate hypoxemia on the pharmacokinetics of metoclopramide and its metabolites in chronically instrumented sheep Kim, John


Hypoxemia is known to induce various physiological changes which can result in pharmacokinetic changes. To examine the effect of acute, moderate hypoxemia in metoclopramide (MCP) pharmacokinetics, a continuous infusion [14 hours] of MCP was administered during pre-hypoxemia (2hr), hypoxemia (6hr) and post-hypoxemia (6hr) in non-pregnant sheep. Hypoxemia was achieved by lowering the ewe's inspired O2 concentration. During the experiment, arterial blood and urine samples were collected. MCP and its mono- and di-deethylated metabolites were measured in these fluid samples using a gas chromatography-mass selective detector (GC-MSD) 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 ± 1.06 to 63.62 ± 1.79 ng/mL, and later decreased to 55.83 ± 1.15 ng/mL during the posthypoxemic recovery period. Plasma mdMCP concentration (32.78 ± 1.73 ng/mL) also increased, compared to the control group (21.20 ± 1.39 ng/mL), during hypoxemia and the subsequent normoxemic period. Renal excretion of MCP and its metabolites significantly decreased during hypoxemia. Increased urine flow with decreased urine osmolality was also observed. Thus the results indicate that acute, moderate hypoxemia affects MCP pharmacokinetics.

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