Rao Lesley K, Flaker Alicia M, Friedel Christina C, Kharasch Evan D
From the Division of Clinical and Translational Research, Department of Anesthesiology (L.K.R., A.M.F., C.C.F., E.D.K.), and Department of Biochemistry and Biophysics (E.D.K.), Washington University in St. Louis, St. Louis, Missouri; and the Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis School of Medicine, St. Louis, Missouri (E.D.K.).
Anesthesiology. 2016 Dec;125(6):1103-1112. doi: 10.1097/ALN.0000000000001392.
At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B66, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B61/1. CYP2B6.6, the protein encoded by the CYP2B66 allele, and liver microsomes from CYP2B66 carriers had diminished ketamine metabolism in vitro. This investigation tested whether humans with the CYP2B66 allele would have decreased clinical ketamine metabolism and clearance.
Thirty volunteers with CYP2B6*1/*1, *1/*6, or *6/*6 genotypes (n = 10 each) received a subsedating dose of oral ketamine. Plasma and urine concentrations of ketamine and the major CYP2B6-dependent metabolites were determined by mass spectrometry. Subjects' self-assessment of ketamine effects were also recorded. The primary outcome was ketamine N-demethylation, measured as the plasma norketamine/ketamine area under the curve ratio. Secondary outcomes included plasma ketamine enantiomer and metabolite area under the plasma concentration-time curve, maximum concentrations, apparent oral clearance, and metabolite formation clearances.
There was no significant difference between CYP2B6 genotypes in ketamine metabolism or any of the secondary outcome measures. Subjective self-assessment did reveal some differences in energy and level of awareness among subjects.
These results show that while the CYP2B6*6 polymorphism results in diminished ketamine metabolism in vitro, this allelic variant did not affect single, low-dose ketamine metabolism, clearance, and pharmacokinetics in vivo. While in vitro drug metabolism studies may be informative, clinical investigations in general are needed to validate in vitro observations.
在治疗浓度下，细胞色素P4502B6（CYP2B6）是体外催化肝脏中氯胺酮N-去甲基化生成去甲氯胺酮的主要P450同工酶。CYP2B6基因具有高度多态性。最常见的变异等位基因CYP2B66与野生型CYP2B61/1相比，肝脏CYP2B6表达和催化活性降低。CYP2B66等位基因编码的蛋白质CYP2B6.6以及来自CYP2B66携带者的肝微粒体在体外氯胺酮代谢能力降低。本研究旨在测试携带CYP2B66等位基因的人临床氯胺酮代谢和清除是否会降低。
30名具有CYP2B6*1/*1、*1/6或6/*6基因型的志愿者（每种基因型10人）接受亚镇静剂量的口服氯胺酮。通过质谱法测定血浆和尿液中氯胺酮及其主要CYP2B6依赖性代谢物的浓度。还记录了受试者对氯胺酮效应的自我评估。主要结局指标是氯胺酮N-去甲基化，以血浆去甲氯胺酮/氯胺酮曲线下面积比衡量。次要结局指标包括血浆氯胺酮对映体和代谢物血浆浓度-时间曲线下面积、最大浓度、表观口服清除率和代谢物生成清除率。
CYP2B6基因型在氯胺酮代谢或任何次要结局指标方面无显著差异。主观自我评估确实显示受试者在精力和意识水平上存在一些差异。
这些结果表明，虽然CYP2B6*6多态性导致体外氯胺酮代谢降低，但这种等位基因变异并不影响单次低剂量氯胺酮在体内的代谢、清除和药代动力学。虽然体外药物代谢研究可能提供信息，但一般需要进行临床研究来验证体外观察结果。
