Genetic polymorphisms of cytochrome P450 enzymes influence metabolism of the antidepressant escitalopram and treatment response
| Autor: | Chi-Shin Wu, Chun Kai Fang, Ming-Hsien Tsai, Shu Chih Liu, Keh Ming Lin, Mei Chun Hsiao, Shao Chun Lu, Chun-Yu Chen, Hwa Sheng Tang, Mong Liang Lu, Winston W. Shen, Yu-Li Liu |
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| Rok vydání: | 2010 |
| Předmět: |
Adult
Male CYP2D6 medicine.medical_specialty Gene Dosage CYP2C19 Citalopram Biology Polymorphism Single Nucleotide Gene dosage Gene Frequency Predictive Value of Tests Internal medicine Genetics medicine Cytochrome P-450 CYP3A Humans Escitalopram Allele Allele frequency Genotyping Chromatography High Pressure Liquid Pharmacology Depressive Disorder Major Models Genetic medicine.disease Cytochrome P-450 CYP2C19 Treatment Outcome Endocrinology Cytochrome P-450 CYP2D6 Antidepressive Agents Second-Generation Molecular Medicine Major depressive disorder Female Aryl Hydrocarbon Hydroxylases Biomarkers medicine.drug |
| Zdroj: | Pharmacogenomics. 11:537-546 |
| ISSN: | 1744-8042 1462-2416 |
| Popis: | 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 *4, *5 and *10 on CYP2D6, *2, *3 and *17 on CYP2C19, and *18 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 CYP3A4*18 and CYP2C19*17 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. |
| Databáze: | OpenAIRE |
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