Pan L, Belpaire F M
Heymans Institute of Pharmacology, University of Gent Medical School, De Pintelaan 185, B-9000 Gent, Belgium.
Eur J Clin Pharmacol. 1999 Oct;55(8):599-604. doi: 10.1007/s002280050679.
To investigate in vitro which CYP isoforms (CYP1A2, CYP2D6 and CYP3A4) are involved in the biotransformation of haloperidol (HAL) and reduced haloperidol (RHAL).
The biotransformation of HAL and RHAL is evaluated by measuring HAL and RHAL remaining after incubation with human liver microsomes and with supersomes from human baculovirus-infected cells expressing human P(450) isoforms. The influence of chemical- and immuno-inhibition of specific isoforms on the disappearance of HAL and RHAL was also studied.
After 60-min incubation of 2 microM and 20 microM HAL or RHAL with human liver microsomes, for HAL, 58% and 64%, respectively, remained in the incubation mixture, for RHAL, 53% and 66%, respectively. Ketoconazole had the most pronounced inhibitory effect on the biotransformation of both substrates, while for quinidine and furafylline there was only a weak or no influence. Anti-CYP3A4 antibodies inhibited strongly the biotransformation of HAL and RHAL, while the influence of anti-CYP2D6 antibodies was much less pronounced. After incubation with supersomes of recombinant CYP3A4, HAL and RHAL disappeared rapidly; disappearance was slow after incubation with CYP2D6 supersomes, and negligible with CYP1A2 supersomes.
The results show that CYP3A4 is the most important CYP isoenzyme involved in the biotransformation of HAL and RHAL, and that the metabolism by CYP2D6 is only a minor pathway; CYP1A2 has no or only a negligible influence.
在体外研究哪些细胞色素P450同工酶（CYP1A2、CYP2D6和CYP3A4）参与氟哌啶醇（HAL）和还原氟哌啶醇（RHAL）的生物转化。
通过测量与人类肝微粒体以及表达人类P450同工酶的人杆状病毒感染细胞的超微粒体孵育后剩余的HAL和RHAL来评估HAL和RHAL的生物转化。还研究了特定同工酶的化学抑制和免疫抑制对HAL和RHAL消失的影响。
将2微摩尔和20微摩尔的HAL或RHAL与人肝微粒体孵育60分钟后，对于HAL，分别有58%和64%留在孵育混合物中，对于RHAL，分别为53%和66%。酮康唑对两种底物的生物转化具有最显著的抑制作用，而奎尼丁和呋拉茶碱只有微弱影响或没有影响。抗CYP3A4抗体强烈抑制HAL和RHAL的生物转化，而抗CYP2D6抗体的影响则不那么明显。与重组CYP3A4的超微粒体孵育后，HAL和RHAL迅速消失；与CYP2D6超微粒体孵育后消失缓慢，与CYP1A2超微粒体孵育后可忽略不计。
结果表明，CYP3A4是参与HAL和RHAL生物转化的最重要的细胞色素P450同工酶，CYP2D6介导的代谢只是一条次要途径；CYP1A2没有影响或影响可忽略不计。
Zotero 插件