Fjordside L, Jeppesen U, Eap C B, Powell K, Baumann P, Brøsen K
Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, Denmark.
Pharmacogenetics. 1999 Feb;9(1):55-60. doi: 10.1097/00008571-199902000-00008.
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.
选择性5-羟色胺再摄取抑制剂氟西汀以消旋混合物的形式给药，R-氟西汀和S-氟西汀在肝脏中分别通过N-去甲基化代谢为R-去甲氟西汀和S-去甲氟西汀。R-氟西汀、S-氟西汀和S-去甲氟西汀都是同等效力的选择性5-羟色胺再摄取抑制剂，但R-去甲氟西汀在这方面的效力要低20倍。消旋氟西汀和去甲氟西汀在体内和体外都是细胞色素P450（CYP）2D6的强效抑制剂，最近的体内研究表明消旋氟西汀是由CYP2D6代谢的。本研究的主要目的是在体内研究CYP2D6对氟西汀和去甲氟西汀的立体选择性代谢。给6名司巴丁代谢不良者和6名司巴丁代谢充分者单次口服一剂氟西汀（60毫克）。对代谢不良者在6周内采集血样，对代谢充分者在3周内采集血样。每周进行一次司巴丁试验。采用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。在代谢不良者中，R-氟西汀和S-氟西汀的口服清除率分别为3.0升/小时和17升/小时，在代谢充分者中的相应值分别为36升/小时和40升/小时。对于两种对映体，表型差异具有统计学意义。在代谢不良者中，R-去甲氟西汀和S-去甲氟西汀的消除半衰期分别为6.9天和17.4天，在代谢充分者中，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，在代谢不良者中，R-对映体和S-对映体的消除半衰期分别为9.5天和6.1天。在代谢充分者中的相应值分别为2.6天和1.1天。同样对于该参数，差异具有统计学意义。本研究表明，CYP2D6催化R-氟西汀和S-氟西汀的代谢，很可能也催化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。
