Kim John, Riggs K Wayne, Rurak Dan W
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada.
Arch Pharm Res. 2002 Oct;25(5):709-17. doi: 10.1007/BF02976949.
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 +/- 1.06 to 63.62 +/- 1.79 ng/mL, and later decreased to 55.83 +/- 1.15 ng/mL during the post-hypoxemic recovery period. Total body clearance (CL(TB)) of MCP was significantly decreased from 274.2 +/- 48.0 L/h to 205.40 +/- 28.2 L/h during hypoxemia, and later restored to 245.8 +/- 44.2 L/h during the post-hypoxemic period. Plasma mono-deethylated MCP concentration (32.78 +/- 1.73 ng/mL) also increased, compared to the control group (21.20 +/- 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.
已知低氧血症会引发各种生理变化，这些变化可能导致药物药代动力学改变。为研究急性中度低氧血症对甲氧氯普胺（MCP）药代动力学的影响，对八只成年绵羊在常氧、低氧及随后的常氧期进行了连续14小时的MCP输注。采集动脉血和尿液样本，以检测对MCP及其去乙基代谢产物药代动力学的影响。使用气相色谱/质谱法对MCP及其单去乙基和双去乙基代谢产物进行定量分析。在三个阶段均达到了MCP的稳态浓度。低氧血症期间，MCP血浆稳态浓度从50.72±1.06 ng/mL显著升至63.62±1.79 ng/mL，随后在低氧血症恢复期降至55.83±1.15 ng/mL。低氧血症期间，MCP的总体清除率（CL(TB)）从274.2±48.0 L/h显著降至205.40±28.2 L/h，随后在低氧血症后阶段恢复至245.8±44.2 L/h。在低氧血症及随后的常氧期，与对照组（21.20±1.39 ng/mL）相比，血浆单去乙基MCP浓度（32.78±1.73 ng/mL）也有所升高。低氧血症期间，MCP及其代谢产物的肾排泄也减少，而尿流量增加，同时尿渗透压降低。因此，结果表明急性中度低氧血症会影响MCP的药代动力学。
