Kharasch E D, Labroo R
Department of Anesthesiology, University of Washington, Seattle 98195.
Anesthesiology. 1992 Dec;77(6):1201-7. doi: 10.1097/00000542-199212000-00022.
Ketamine is used clinically as a racemic mixture of optical isomers that differ in their analgesic properties and psychomimetic effects. Administered individually, or together as the racemate, ketamine enantiomers differ in their hepatic clearance and duration of anesthetic effect. S(+) ketamine exhibits a greater clearance and faster anesthetic recovery compared to the racemate and a greater clearance compared to R(-) ketamine. Ketamine undergoes extensive hepatic metabolism, primarily via N-demethylation to norketamine, yet little is known about the human metabolism of ketamine enantiomers. The purpose of this investigation therefore was to characterize ketamine racemate and enantiomer metabolism by human liver and to test the hypothesis that differences in hepatic ketamine enantiomer metabolism can account for observed differences in ketamine enantiomer pharmacokinetics. Ketamine N-demethylation by microsomes from three human livers was measured by gas chromatography-mass spectrometry. At ketamine concentrations typically achieved during anesthesia (5 microM), the rate of S(+) ketamine demethylation was 20% greater than that of R(-) ketamine and 10% greater than that of the racemate (P < .05). At all ketamine concentrations, the rate of racemate demethylation was less than the sum of the rates for the individual enantiomers, reflecting a metabolic enantiomeric interactin whereby one ketamine enantiomer inhibits the metabolism of the other enantiomer. N-demethylation of racemic ketamine and each enantiomer was catalyzed by two apparent enzymes, a high affinity-low capacity enzyme (Km1 30-50 microM, Vmax1 2-6 nmoles.min-1 x nmole-1) and a low affinity-high capacity enzyme (Km2 600-800 microM, Vmax2 9-15 nmoles.min-1 x nmole-1).(ABSTRACT TRUNCATED AT 250 WORDS)
氯胺酮在临床上用作外消旋混合物，其光学异构体的镇痛特性和拟精神效应有所不同。单独给药或以消旋体形式一起给药时，氯胺酮对映体的肝脏清除率和麻醉效果持续时间存在差异。与消旋体相比，S(+)氯胺酮表现出更高的清除率和更快的麻醉恢复，与R(-)氯胺酮相比清除率更高。氯胺酮经历广泛的肝脏代谢，主要通过N-去甲基化生成去甲氯胺酮，但关于氯胺酮对映体的人体代谢知之甚少。因此，本研究的目的是表征人肝脏对氯胺酮消旋体和对映体的代谢，并检验以下假设：肝脏中氯胺酮对映体代谢的差异可解释氯胺酮对映体药代动力学中观察到的差异。通过气相色谱-质谱法测量了来自三个人肝脏的微粒体对氯胺酮的N-去甲基化。在麻醉期间通常达到的氯胺酮浓度（5 microM）下，S(+)氯胺酮的去甲基化速率比R(-)氯胺酮高20%，比消旋体高10%（P <.05）。在所有氯胺酮浓度下，消旋体的去甲基化速率低于各个对映体速率之和，这反映了一种代谢对映体相互作用，即一种氯胺酮对映体抑制另一种对映体的代谢。外消旋氯胺酮和每种对映体的N-去甲基化由两种明显的酶催化，一种是高亲和力-低容量酶（Km1 30-50 microM，Vmax1 2-6 nmoles.min-1 x nmole-1）和一种低亲和力-高容量酶（Km2 600-800 microM，Vmax2 9-15 nmoles.min-1 x nmole-1）。（摘要截短于250字）
