Stereoselective and regiospecific hydroxylation of ketamine and norketamine.
Stereoselective and regiospecific hydroxylation of ketamine and norketamine.
复制标题
DOI：
10.3109/00498254.2012.685777
复制
发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Wainer IW
中科院分区：
文献类型：
--
作者：
Desta Z;Moaddel R;Ogburn ET;Xu C;Ramamoorthy A;Venkata SL;Sanghvi M;Goldberg ME;Torjman MC;Wainer IW
目的是确定负责氯胺酮（（R，S）-Ket）立体选择性和区域特异性羟基化为非对映体羟基氯胺酮的细胞色素P450（CYP），（2S，6S;2R，6R）-HK（5a）和（2S，6 R; 2 R，6S）-HK（5 b）和去甲氯胺酮（（R，S）-norKet）转化为羟基去甲氯胺酮，（2S，6S;2R，6R）-HNK（4a）、（2S，6R;2R，6S）-HNK（4b）、（2S，5S;2R，5R）-HNK（4c）、（2S，4S;2R，4R）-HNK（4d）、（2S，4R;2R，4S）-HNK（4e）、（2S，5R;2R，5S）-HNK（4f）。将Ket和norKet的对映体与HLM一起孵育并表达CYP。使用LC/MS/MS鉴定和定量代谢物，并使用单位点Michaelis-Menten、Hill或底物抑制方程估计表观动力学常数。5a主要通过CYP 2A 6由（S）-Ket形成，并通过CYP 2B 6 N-脱甲基化为4a。5 b由（R）-和（S）-Ket通过CYP 3A 4/3A 5形成，并通过多种酶N-去甲基化为4 b。norKet孵育产生4a、4c和4f以及少量的4d和4 e。CYP 2A 6和CYP 2B 6是形成4a、4d和4f的主要酶，CYP 3A 4/3A 5是形成4 e的主要酶。在norKet孵育物中未检测到4 b代谢物。在接受（R，S）-Ket的患者的血浆样本中检测到5a和4 b，表明5a和5 b是重要的Ket代谢物。观察到HNK浓度的较大变化，表明药物遗传学和/或代谢药物相互作用可能在治疗反应中发挥作用。
The objective was to determine the cytochrome P450s (CYPs) responsible for the stereoselective and regiospecific hydroxylation of ketamine ((R,S)-Ket) to diastereomeric hydroxyketamines, (2S,6S;2R,6R)-HK (5a) and (2S,6R;2R,6S)-HK (5b) and norketamine ((R,S)-norKet) to hydroxynorketamines, (2S,6S;2R,6R)-HNK (4a), (2S,6R;2R,6S)-HNK (4b), (2S,5S;2R,5R)-HNK (4c), (2S,4S;2R,4R)-HNK (4d), (2S,4R;2R,4S)-HNK (4e), (2S,5R;2R,5S)-HNK (4f). The enantiomers of Ket and norKet were incubated with HLMs and expressed CYPs. Metabolites were identified and quantified using LC/MS/MS and apparent kinetic constants estimated using single-site Michaelis-Menten, Hill or substrate inhibition equation. 5a was predominantly formed from (S)-Ket by CYP2A6 and N-demethylated to 4a by CYP2B6. 5b was formed from (R)- and (S)-Ket by CYP3A4/3A5 and N-demethylated to 4b by multiple enzymes. norKet incubation produced 4a, 4c and 4f and minor amounts of 4d and 4e. CYP2A6 and CYP2B6 were the major enzymes responsible for the formation of 4a, 4d and 4f, and CYP3A4/3A5 for the formation of 4e. The 4b metabolite was not detected in the norKet incubates. 5a and 4b were detected in plasma samples from patients receiving (R,S)-Ket, indicating that 5a and 5b are significant Ket metabolites. Large variations in HNK concentrations were observed suggesting that pharmacogenetics and/or metabolic drug interactions may play a role in therapeutic response.
登录
查看更多内容
影响因子：
8.8
作者：
Sigtermans, Marnix;Dahan, Albert;Olofsen, Erik
通讯作者：
Olofsen, Erik
影响因子：
8.8
作者：
KHARASCH, ED;HERRMANN, S;LABROO, R
通讯作者：
LABROO, R
影响因子：
3.4
作者：
Wang, ZQ;Hall, SD;Gorski, JC
通讯作者：
Gorski, JC
影响因子：
3.6
作者：
Lester, Laeben;Braude, Darren A.;Crandall, Cameron S.
通讯作者：
Crandall, Cameron S.
影响因子：
3.7
作者：
Sabia M;Hirsh RA;Torjman MC;Wainer IW;Cooper N;Domsky R;Goldberg ME
通讯作者：
Goldberg ME