Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine.
Identification of the human cytochromes P450 responsible for the in vitro formation of the major oxidative metabolites of the antipsychotic agent olanzapine.
复制标题
DOI：
--
复制
发表时间：
1996-02
期刊：
影响因子：
--
通讯作者：
Barbara J. Ring;J. Catlow;T. Lindsay;T. Gillespie;L. Roskos;B. Cerimele;Steven P. Swanson;M. Hamman;S. Wrighton
中科院分区：
文献类型：
--
作者：
Barbara J. Ring;J. Catlow;T. Lindsay;T. Gillespie;L. Roskos;B. Cerimele;Steven P. Swanson;M. Hamman;S. Wrighton
研究了2-羟基甲基奥氮平（2-OH奥氮平）、4'- n -氧化物奥氮平（N-O奥氮平）和4'- n -去甲基奥氮平（NdM奥氮平）的体外生成动力学。观察了2-OH和NdM奥氮平形成的双相动力学。负责2-OH奥氮平形成的高亲和力酶在两个人肝脏样品中显示出0.2微升/分钟/毫克的内在清除率（CLint）。两个人肝脏样品形成NdM奥氮平的CLint为1.0微升/分钟/毫克的高亲和力酶。氮氧奥氮平的生成在300 μ m奥氮平下呈线性，CLint为0.32 ~ 1.70 μ l /min/mg。7-羟基奥氮平（7-OH奥氮平）形成的表观Km为24.2微米。2-OH奥氮平的形成速率与CYP2D6水平和活性相关，并且在很大程度上是由cdna表达的CYP2D6形成的。氮氧奥氮平的形成与人肝脏含黄素单加氧酶（FMO3）水平和活性相关。NdM奥氮平和7-OH奥氮平的形成与CYP1A2的催化活性相关，并且在很大程度上是通过表达CYP1A2形成的。这些结果表明，CYP1A2催化NdM奥氮平和7-OH奥氮平生成，CYP2D6催化2-OH奥氮平生成，FMO3催化N-O奥氮平生成。
The formation kinetics of 2-hydroxymethyl olanzapine (2-OH olanzapine), 4'-N-oxide olanzapine (N-O olanzapine) and 4'-N-desmethyl olanzapine (NdM olanzapine) were analyzed in vitro. Biphasic kinetics were observed for formation of 2-OH and NdM olanzapine. The high-affinity enzyme responsible for 2-OH olanzapine formation by two human liver samples exhibited an intrinsic clearance (CLint) of 0.2 microliter/min/mg. NdM olanzapine formation by two human liver samples exhibited a CLint of 1.0 microliter/min/mg for the high affinity enzyme. The formation of N-O olanzapine was linear up to 300 microM olanzapine, yielding a CLint of 0.32 to 1.70 microliters/min/mg. The formation of 7-hydroxy olanzapine (7-OH olanzapine) exhibited an apparent Km of 24.2 microM. The rates of 2-OH olanzapine formation correlated with CYP2D6 levels and activity, and it was formed to the greatest extent by cDNA-expressed CYP2D6. N-O olanzapine formation correlated with human liver flavin-containing monooxygenase (FMO3) levels and activity. NdM olanzapine and 7-OH olanzapine formation correlated with CYP1A2 catalytic activities and they were formed to the greatest extent by expressed CYP1A2. These results suggest that CYP1A2 catalyzes NdM olanzapine and 7-OH olanzapine formation, CYP2D6 catalyzes 2-OH olanzapine formation and FMO3 catalyzes N-O olanzapine formation.