The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine
The stereoselective metabolism of fluoxetine in poor and extensive metabolizers of sparteine
复制标题
DOI：
10.1097/00008571-199902000-00008
复制
发表时间：
1999-02-01
期刊：
影响因子：
--
通讯作者：
Brosen, K
中科院分区：
文献类型：
--
作者：
Fjordside, L;Jeppesen, U;Brosen, K
选择性5-羟色胺再摄取抑制剂氟西汀作为外消旋混合物给药，R-和S-氟西汀在肝脏中通过N-去甲基化分别代谢为R-和S-去甲氟西汀，R-和S-氟西汀和S-去甲氟西汀是同样有效的选择性5-羟色胺再摄取抑制剂，但R-去甲氟西汀在这方面的效力低20倍。外消旋氟西汀和去甲氟西汀是细胞色素P450（CYP）2D 6的有效抑制剂，近年来的体内研究表明，外消旋氟西汀通过CYP 2D 6代谢。本研究的主要目的是探讨氟西汀和去甲氟西汀在体内的立体选择性代谢。单剂量口服氟西汀（60毫克）给予6个弱和6个快代谢的鹰爪豆碱。在6周内采集慢代谢型患者的血液样本，在3周内采集快代谢型患者的血液样本。每周进行一次Sparteine试验，通过立体选择性气相色谱-质谱法测定氟西汀和去甲氟西汀的R-和S-对映体。在弱代谢者中，R-和S-氟西汀的口服清除率分别为3.0 l/h和17 l/h，在快代谢者中的相应值分别为36 l/h和40 l/h，对于两种对映体，表型差异具有统计学意义。在弱代谢者中，R-和S-去甲氟西汀的消除半衰期分别为6.9天和17.4天，在快代谢者中，两种对映体的消除半衰期均为5.5天，仅S-去甲氟西汀存在显著的表型差异。对于氟西汀，R-和S-对映异构体在弱代谢型中的消除半衰期分别为9.5和6.1天，在快代谢型中的相应值分别为2.6和1.1天，对于该参数，差异也具有统计学显著性，该研究表明，CYP 2D 6催化R-和S-氟西汀的代谢，并且很可能催化S-去甲氟西汀的进一步代谢，但不催化R-去甲氟西汀的代谢，药理遗传学9：55-60（C）1999 Lippincott威廉姆斯&威尔金斯。
The selective serotonin reuptake inhibitor fluoxetine is administered as a racemic mixture, and R- and S-fluoxetine are metabolized in the liver by N-demethylation to R- and S-norfluoxetine, respectively, R- and S-fluoxetine and S-norfluoxetine are equally potent selective serotonin reuptake inhibitors, but R-norfluoxetine is 20-fold less potent in this regard. Racemic fluoxetine and norfluoxetine are potent inhibitors of cytochrome P450 (CYP) 2D6 in vivo and in vitro and recent, studies in vivo have shown that racemic fluoxetine is metabolized by CYP2D6, The primary aim of the present study was to investigate the stereoselective metabolism of fluoxetine and norfluoxetine by CYP2D6 in vivo. A single oral dose of fluoxetine (60 mg) was administered to six poor and six extensive metabolizers of sparteine. Blood samples were collected during 6 weeks for poor metabolizers and 3 weeks for extensive metabolizers. Once a week a sparteine test was performed, The R- and S-enantiomers of fluoxetine and norfluoxetine were determined by a stereoselective gas chromatography-mass spectroscopy method. In the poor metabolizers, the oral clearance of R- and S-fluoxetine was 3.0 l/h and 17 l/h, respectively, the corresponding values in the extensive metabolizers were 36 l/h and 40 l/h, respectively, For both enantiomers, the phenotype difference was statistically significant. In poor metabolizers, the elimination half-lives were 6.9 days and 17.4 days for R- and S-norfluoxetine, respectively, and in the extensive metabolizers it was 5.5 days for both enantiomers, a significant phenotypical difference only for S-norfluoxetine. For fluoxetine the elimination half-lives were 9.5 and 6.1 days in poor metabolizers for the R- and S-enantiomer, respectively, The corresponding values in the extensive metabolizers were 2.6 and 1.1 days, respectively, Also for this parameter, the differences were statistically significant, This study shows that CYP2D6 catalyses the metabolism of R- and S-fluoxetine and most likely the further metabolism of S-norfluoxetine but not of R-norfluoxetine, Pharmacogenetics 9:55-60 (C) 1999 Lippincott Williams & Wilkins.