Stereoselective biotransformation of ketamine in equine liver and lung microsomes.
Stereoselective biotransformation of ketamine in equine liver and lung microsomes.
复制标题
氯胺酮在马肝和肺微粒体中的立体选择性生物转化。
DOI：
10.1111/j.1365-2885.2008.00972.x
复制
发表时间：
2008
影响因子：
1.3
通讯作者：
Mevissen,M
中科院分区：
文献类型：
--
作者：
Schmitz,A;Portier,CJ;Thormann,W;Theurillat,R;Mevissen,M
立体选择性必须考虑到氯胺酮的药效学和药代动力学特征。研究了氯胺酮在马微粒体中的立体选择性生物转化。利用马肝脏和肺微粒体构建浓度随时间变化的曲线，测定不同底物浓度下的酶活性。采用对映选择毛细管电泳法测定R/S‐氯胺酮和R/S‐诺氯胺酮的浓度。基于Hill动力学的两相模型用于分析R/S‐氯胺酮转化为R/S‐诺氯胺酮，并在第二步转化为R/S‐下游代谢物。在肝脏和肺微粒体中，R -氯胺酮的水平在所有时间点都超过S -氯胺酮，S -诺氯胺酮在低于最大浓度的时间点超过R -诺氯胺酮。在肝脏和肺微粒体中，当S‐氯胺酮与S‐氯胺酮外消旋体进行比较时，观察到S‐诺氯胺酮和R‐诺氯胺酮形成的酶速度（Vmax）以及S‐诺氯胺酮形成的Vmax之间存在显著差异。我们在体外对微粒体反应的研究表明，马体内的立体选择性氯胺酮生物转化发生在肝脏和肺部，在R -氯胺酮存在的情况下，S -氯胺酮的消除速度较慢。他们的体外参数与肝脏和肺器官清除率的比例与先前发表的体内数据非常吻合，并证实了肺首过效应。
Stereoselectivity has to be considered for pharmacodynamic and pharmacokinetic features of ketamine. Stereoselective biotransformation of ketamine was investigated in equine microsomesin vitro.Concentration curves were constructed over time, and enzyme activity was determined for different substrate concentrations using equine liver and lung microsomes. The concentrations of R/S‐ketamine and R/S‐norketamine were determined by enantioselective capillary electrophoresis. A two‐phase model based on Hill kinetics was used to analyze the biotransformation of R/S‐ketamine into R/S‐norketamine and, in a second step, into R/S‐downstream metabolites.In liver and lung microsomes, levels of R‐ketamine exceeded those of S‐ketamine at all time points and S‐norketamine exceeded R‐norketamine at time points below the maximum concentration. In liver and lung microsomes, significant differences in the enzyme velocity (Vmax) were observed between S‐ and R‐norketamine formation and betweenVmaxof S‐norketamine formation when S‐ketamine was compared to S‐ketamine of the racemate.Our investigations in microsomal reactionsin vitrosuggest that stereoselective ketamine biotransformation in horses occurs in the liver and the lung with a slower elimination of S‐ketamine in the presence of R‐ketamine. Scaling of thein vitroparameters to liver and lung organ clearances provided an excellent fit with previously publishedin vivodata and confirmed a lung first‐pass effect.