Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response

Ming Hsien Tsai, Keh Ming Lin, Mei Chun Hsiao, Winston W. Shen, Mong Liang Lu, Hwa Sheng Tang, Chun Kai Fang, Chi Shin Wu, Shao Chun Lu, Shu Chih Liu, Chun Yu Chen, Yu Li Liu

研究成果: 雜誌貢獻文章同行評審

95 引文 斯高帕斯(Scopus)

摘要

Aims: The antidepressant escitalopram (S-CIT) is metabolized by the cytochrome-P450 (CYP) enzymes CYP 2D6, 2C19 and 3A4. This study evaluated the impact of CYP2D6, 2C19 and 3A4 genetic polymorphisms on plasma concentrations of S-CIT and patient treatment response. Materials & methods: A total of 100 patients diagnosed with major depressive disorder were recruited to the study and their depression symptoms were assessed using the Hamilton Depression Rating Scale. The genetic polymorphisms ß4, ß5 and ß10 on CYP2D6, ß2, ß3 and ß17 on CYP2C19, and ß18 on CYP3A4 were selected based on their function and respective allele frequencies in Asian populations. Polymorphisms were analyzed using the SNPstream® genotyping system, PCR and direct sequencing methods. The steady-state serum concentrations of S-CIT and its metabolites S-desmethylcitalopram and S-didesmethylcitalopram were analyzed by HPLC. According to semiquantitative gene dose (SGD) and gene dose (GD) models for allele combinations of these polymorphisms, CYP2D6 was clustered into intermediate (0.5, 1 and 1.5 SGD) and extensive (2 SGD) metabolizers, while CYP2C19 was clustered into poor (0 GD) and extensive (1 and 2 GDs) metabolizers. Results: The group of patients with intermediate CYP2D6 metabolism (0.5 SGD) had a significantly higher frequency of remitters from major depressive disorder during the 8-week treatment (p = 0.0001). Furthermore, CYP2C19 poor metabolizers had significantly higher S-CIT serum levels than did extensive metabolizers at weeks 2, 4 and 8 (p <0.05). The allele frequencies in CYP3A4ß18 and CYP2C19ß17 were too low to permit further subgroup analyses. Conclusion: Our results suggest that the genetic polymorphisms in CYP2C19 may be influencing S-CIT serum concentrations, and that specific CYP2D6 polymorphisms may be predicting patient treatment outcomes based on gene dosage analyses.
原文英語
頁(從 - 到)537-546
頁數10
期刊Pharmacogenomics
11
發行號4
DOIs
出版狀態已發佈 - 四月 2010

ASJC Scopus subject areas

  • 分子醫學
  • 遺傳學
  • 藥理

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