CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes.
CYP3A is responsible for N-dealkylation of haloperidol and bromperidol and oxidation of their reduced forms by human liver microsomes.
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CYP3A 负责氟哌啶醇和溴哌啶醇的 N-脱烷基化以及人肝微粒体对其还原形式的氧化。
DOI：
10.1016/s0024-3205(00)00874-2
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发表时间：
2000
期刊：
影响因子：
6.1
通讯作者：
Shinichi Kobayashi
中科院分区：
文献类型：
--
作者：
Tomonori Tateishi;Minoru Watanabe;T. Kumai;Masami Tanaka;H. Moriya;S. Yamaguchi;Tetsuo Satoh;Shinichi Kobayashi
我们研究了氟哌啶醇、溴哌啶醇及其还原形式在人肝微粒体中的生物转化。硝苯地平氧化（CYP3A）活性与氟哌啶醇和溴哌啶醇的n -脱烷基率及其还原形式的氧化率显著相关，而乙氧基间苯甲醚o -去乙基化（CYP1A2）活性和右美沙芬o -去乙基化（CYP2D6）活性均不相关。在化学和免疫抑制研究中，只有troleandomycin和抗cyp3a4血清抑制4-氟苯甲酰丙酸（氟哌啶醇和溴哌啶醇的代谢物）的形成速率和反氧化速率。在检测的10种重组异构体中，只有CYP3A4具有催化活性。溴哌啶醇n -脱烷基反应和还原性溴哌啶醇再氧化反应的Vmax和Km值分别与氟哌啶醇和还原性氟哌啶醇相似。本研究表明CYP3A在溴哌啶醇和溴哌啶醇的n -脱烷基和氧化回溴哌啶醇中起主要作用，提示通过抑制或诱导改变体内CYP3A活性可能会影响氟哌啶醇和溴哌啶醇的药代动力学和治疗效果。
We studied the biotransformation of haloperidol, bromperidol and their reduced forms by human liver microsomes. Nifedipine oxidation (CYP3A) activity correlated significantly with N-dealkylation rates of haloperidol and bromperidol and oxidation rates of their reduced forms, while neither ethoxyresorufin O-deethylation (CYP1A2) activity nor dextromethorphan O-deethylation (CYP2D6) activity did. In chemical and immunoinhibition studies, only troleandomycin and anti-CYP3A4 serum inhibited both formation rates of 4-fluorobenzoylpropionic acid, a metabolite of haloperidol and bromperidol, and back oxidation rates. Among 10 recombinant isoforms examined, only CYP3A4 showed catalytic activity. The Vmax and Km values of N-dealkylation of bromperidol and reoxidation of reduced bromperidol were similar to those of haloperidol and reduced haloperidol, respectively. The present study indicates that CYP3A plays a major role in N-dealkylation of and oxidation back to bromperidol as well as haloperidol and suggests that modification of in vivo CYP3A activity by inhibition or induction may affect the pharmacokinetics and therapeutic effects of haloperidol and bromperidol.