Scordo Maria G, Spina Edoardo, Dahl Marja-Liisa, Gatti Giuliana, Perucca Emilio
Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, University of Messina, Italy.
Basic Clin Pharmacol Toxicol. 2005 Nov;97(5):296-301. doi: 10.1111/j.1742-7843.2005.pto_194.x.
The antidepressant fluoxetine is administered as racemic mixture of two enantiomers (S- and R-fluoxetine). While S- and R-fluoxetine are equipotent in blocking serotonin reuptake, the enantiomers of the demethylated metabolite, norfluoxetine, show marked differences in pharmacological activity, S-norfluoxetine being about 20 times as potent as R- norfluoxetine as a serotonin reuptake inhibitor. In vitro and in vivo data suggest that the metabolism of fluoxetine to norfluoxetine is stereoselective and mediated, at least in part, by the polymorphic cytochrome P450 (CYP) isoenzymes CYP2D6, CYP2C9 and CYP2C19. In the present study, the influence of CYP2D6, CYP2C9 and CYP2C19 polymorphisms on the steady-state plasma concentrations of fluoxetine and norfluoxetine enantiomers was evaluated in 78 patients receiving chronic fluoxetine treatment (10-60 mg/day). The plasma concentrations of fluoxetine and norfluoxetine enantiomers were measured and CYP2D6, CYP2C9 and CYP2C19 genotypes were analyzed. No statistically significant relationship was identified between CYP2D6 or CYP2C19 genotypes and the dose normalised plasma concentrations of any of the enantiomers or the active moiety (i.e. the sum of S-fluoxetine, R-fluoxetine and S-norfluoxetine). However, the plasma concentration of S-norfluoxetine was very low in the only CYP2D6 poor metaboliser. Furthermore, the median S-norfluoxetine/S-fluoxetine ratios were higher in homozygous than in heterozygous extensive metabolisers (P<0.05). Among homozygous extensive metabolizers for CYP2D6, patients homozygous for CYP2C9*1 had lower dose-normalized R-fluoxetine concentrations and lower active moiety levels compared with those carrying detrimental CYP2C9 alleles (P<0.05). These results suggest that CYP2D6 and CYP2C9 polymorphisms contribute to the interindividual variability in fluoxetine pharmacokinetics at steady-state.
抗抑郁药氟西汀是以两种对映体（S-氟西汀和R-氟西汀）的外消旋混合物形式给药的。虽然S-氟西汀和R-氟西汀在阻断5-羟色胺再摄取方面具有同等效力，但去甲基代谢产物去甲氟西汀的对映体在药理活性上表现出显著差异，S-去甲氟西汀作为5-羟色胺再摄取抑制剂的效力约为R-去甲氟西汀的20倍。体外和体内数据表明，氟西汀代谢为去甲氟西汀具有立体选择性，并且至少部分由多态性细胞色素P450（CYP）同工酶CYP2D6、CYP2C9和CYP2C19介导。在本研究中，对78例接受慢性氟西汀治疗（10 - 60mg/天）的患者评估了CYP2D6、CYP2C9和CYP2C19基因多态性对氟西汀和去甲氟西汀对映体稳态血浆浓度的影响。测量了氟西汀和去甲氟西汀对映体的血浆浓度，并分析了CYP2D6、CYP2C9和CYP2C19基因型。在CYP2D6或CYP2C19基因型与任何对映体或活性部分（即S-氟西汀、R-氟西汀和S-去甲氟西汀的总和）的剂量标准化血浆浓度之间未发现统计学上的显著关系。然而，在唯一的CYP2D6慢代谢者中，S-去甲氟西汀的血浆浓度非常低。此外，纯合子广泛代谢者的S-去甲氟西汀/S-氟西汀中位数比值高于杂合子广泛代谢者（P<0.05）。在CYP2D6纯合子广泛代谢者中，与携带有害CYP2C9等位基因的患者相比，CYP2C9*1纯合子患者的剂量标准化R-氟西汀浓度和活性部分水平较低（P<0.05）。这些结果表明，CYP2D6和CYP2C9基因多态性导致了氟西汀稳态药代动力学的个体间差异。
