大鼠对氯胺酮耐受性的发展及肝脏代谢的意义。

The development of tolerance to ketamine in rats and the significance of hepatic metabolism.

Livingston A, Waterman A E

Br J Pharmacol. 1978 Sep;64(1):63-9. doi: 10.1111/j.1476-5381.1978.tb08641.x.

Abstract

A decrease in sleeping time in rats pretreated with ten daily doses of ketamine compared to controls is shown. 2. This decrease in sleeping time is associated with a more rapid decrease in circulating and brain levels of ketamine and its N-demethylated metabolite and higher levels of the subsequent oxidation metabolite in the pretreated animals. 3. Metabolism of ketamine to its N-demethylated metabolite by liver homogenates in vitro was more rapid when the livers were obtained from ketamine pretreated rats. 4. Microsomal preparations from rat liver were capable of metabolizing ketamine to its N-demethylated metabolite and this metabolite to the subsequent oxidation metabolite in vitro. The Vmax and Km for the first reaction calculated from loss of substrate were 433 mol mg-1 protein h-1 and 0.133 mM respectively and 199 nmol mg-1 protein h-1 and 0.121 mM for the second reaction. 5. The results indicate that tolerance to ketamine in rats is associated with increased hepatic metabolism which can also be demonstrated in vitro in liver homogenates.

摘要

结果显示，与对照组相比，每日接受十次氯胺酮预处理的大鼠睡眠时间减少。2. 睡眠时间的减少与预处理动物体内氯胺酮及其N-去甲基代谢物的循环和脑内水平更快下降以及随后氧化代谢物的更高水平有关。3. 当从氯胺酮预处理的大鼠获取肝脏时，体外肝匀浆将氯胺酮代谢为其N-去甲基代谢物的速度更快。4. 大鼠肝脏的微粒体制剂能够在体外将氯胺酮代谢为其N-去甲基代谢物，并将该代谢物进一步代谢为随后的氧化代谢物。根据底物损失计算，第一个反应的Vmax和Km分别为433 μmol mg-1蛋白质 h-1和0.133 mM，第二个反应的Vmax和Km分别为199 nmol mg-1蛋白质 h-1和0.121 mM。5. 结果表明，大鼠对氯胺酮的耐受性与肝脏代谢增加有关，这在体外肝匀浆中也得到证实。