抑郁症患者CYP2D6基因多态性与文拉法辛代谢的相关性研究
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摘要
目的:探讨汉族抑郁症患者CYP2D6基因多态性对文拉法辛体内代谢的影响。方法:以79名抑郁症住院患者为研究对象,采用液相色谱-质谱/质谱联用技术测定患者体内文拉法辛及去甲文拉法辛血药浓度,采用sanger测序对患者CYP2D6*4基因(rs3892097)、CYP2D6*5基因(基因缺失)、CYP2D6*10基因(rs1065852)和CYP2D6*14基因(rs5030865)进行SNPs分型。结果:(1)CYP2D6*4、CYP2D6*5、CYP2D6*14 3个基因的突变检出率为0%。根据CYP2D6*10(rs1065852)基因分型结果将患者分为3组:CC组(15例,19.0%)、CT组(25例,31.6%)和TT组(39例,49.4%),其中T等位基因突变频率为65.2%;(2)3组间C_(VEN)、C_(ODV)、剂量校正前后C_(VEN)+C_(ODV)浓度差异无统计学意义;CC、CT和TT组C_(ODV)/C_(VEN)分别为6.0、4.0和3.0,其中CC与TT组间差异有高度统计意义(P<0.01),CC与CT组间差异有统计意义(P<0.05)。(3)不同性别组间C_(ODV)和剂量校正前后的C_(VEN)+C_(ODV)差异有统计意义:女性组C_(ODV)(368.6 ng·mL~(-1))高出男性组(267.0 ng·mL~(-1))38.1%;女性组C_(VEN)+C_(ODV)(499.3 ng·mL~(-1))高出男性组(406.7 ng·mL~(-1))22.8%;女性组剂量校正后C_(VEN)+C_(ODV)(2.5 ng·mL~(-1)·mg~(-1))高出男性组(2.1 ng·mL~(-1)·mg~(-1))19.0%。结论:研究未发现不同CYP2D6基因型组间药物浓度差异有统计意义,但不同基因型组间文拉法辛代谢率(C_(ODV)/C_(VEN))差异有显著性。文拉法辛体内代谢存在性别差异,但临床疗效是否有差异有待进一步研究;相对于男性患者,女性患者暴露于更高的药物浓度之下,发生药物不良反应的风险更高,因此临床治疗女性患者时剂量调整需更加缓慢和谨慎。
OBJECTIVE To investigate the effect of CYP2 D6 gene polymorphism on venlafaxine metabolism in Chinese Han patients with depression. METHODS Plasma concentration of Venlafaxine and O-desmethylvenlafaxine was determined with liquid chromatography-mass spectrometry/mass spectrometry and the genotype of CYP2 D6 * 4(rs3892097), CYP2 D6 * 5 genes(gene deletion), CYP2 D6 * 10 genes(rs1065852) and CYP2 D6 * 14(rs5030865) were analysed with sanger sequencing in 79 inpatients with depression. RESULTS(1)The mutation detection rate of CYP2 D6* 4, CYP2 D6* 5 and CYP2 D6*14 was 0%. According to the genotyping of CYP2 D6*10(rs1065852), the patients were divided into three groups: CC group(15, 19.0%), CT group(25,31.6%)and TT group(39, 49.4%), in which the frequency of T allele mutation was 65.2%.(2)No significant difference was observed between three groups in C_(VEN), C_(ODV), C_(VEN)+C_(ODV) and dose-adjusted C_(VEN)+C_(ODV). C_(ODV)/C_(VEN) in CC, TT and CT group respectively was 6.0, 4.0 and 3.0,in which the difference between CC and TT groups was highly statistically significant(P < 0.01) and a statistically significant difference was observed between CC and CT group(P < 0.05). 3 There was a statistically significant difference between C_(ODV),C_(VEN)+C_(ODV) and dose-adjusted C_(VEN)+C_(ODV) in different gender groups: C_(ODV) of female patients(368.6 ng·mL~(-1))was 38.1% higher than that of male patients(267.0 ng·mL~(-1));C_(VEN)+C_(ODV) of female patients(499.3 ng·mL~(-1)) was 22.8% higher than that of male patients(406.7 ng·mL~(-1)).Dose-adjusted C_(VEN)+C_(ODV) of female patients(2.5 ng·mL~(-1)·mg~(-1)) was 19.0% higher than that of male patients(2.1 ng·mL~(-1)·mg~(-1)).CONCLUSION No significant difference was observed in drug concentrations between different CYP2 D6 genotype groups, but there was a statistically significant difference in venlafaxine metabolic rate(C_(ODV)/C_(VEN)) between different genotype groups. There is a gender difference in the metabolism of venlafaxine in vivo, but whether there is a difference in clinical efficacy remains to be further studied; compared to male patients, female patients are exposed to higher drug concentrations and have a higher risk of adverse drug reactions. Therefore, dose adjustments need to be made more slowly and cautiously when treating female patients.
OBJECTIVE To investigate the effect of CYP2 D6 gene polymorphism on venlafaxine metabolism in Chinese Han patients with depression. METHODS Plasma concentration of Venlafaxine and O-desmethylvenlafaxine was determined with liquid chromatography-mass spectrometry/mass spectrometry and the genotype of CYP2 D6 * 4(rs3892097), CYP2 D6 * 5 genes(gene deletion), CYP2 D6 * 10 genes(rs1065852) and CYP2 D6 * 14(rs5030865) were analysed with sanger sequencing in 79 inpatients with depression. RESULTS(1)The mutation detection rate of CYP2 D6* 4, CYP2 D6* 5 and CYP2 D6*14 was 0%. According to the genotyping of CYP2 D6*10(rs1065852), the patients were divided into three groups: CC group(15, 19.0%), CT group(25,31.6%)and TT group(39, 49.4%), in which the frequency of T allele mutation was 65.2%.(2)No significant difference was observed between three groups in C_(VEN), C_(ODV), C_(VEN)+C_(ODV) and dose-adjusted C_(VEN)+C_(ODV). C_(ODV)/C_(VEN) in CC, TT and CT group respectively was 6.0, 4.0 and 3.0,in which the difference between CC and TT groups was highly statistically significant(P < 0.01) and a statistically significant difference was observed between CC and CT group(P < 0.05). 3 There was a statistically significant difference between C_(ODV),C_(VEN)+C_(ODV) and dose-adjusted C_(VEN)+C_(ODV) in different gender groups: C_(ODV) of female patients(368.6 ng·mL~(-1))was 38.1% higher than that of male patients(267.0 ng·mL~(-1));C_(VEN)+C_(ODV) of female patients(499.3 ng·mL~(-1)) was 22.8% higher than that of male patients(406.7 ng·mL~(-1)).Dose-adjusted C_(VEN)+C_(ODV) of female patients(2.5 ng·mL~(-1)·mg~(-1)) was 19.0% higher than that of male patients(2.1 ng·mL~(-1)·mg~(-1)).CONCLUSION No significant difference was observed in drug concentrations between different CYP2 D6 genotype groups, but there was a statistically significant difference in venlafaxine metabolic rate(C_(ODV)/C_(VEN)) between different genotype groups. There is a gender difference in the metabolism of venlafaxine in vivo, but whether there is a difference in clinical efficacy remains to be further studied; compared to male patients, female patients are exposed to higher drug concentrations and have a higher risk of adverse drug reactions. Therefore, dose adjustments need to be made more slowly and cautiously when treating female patients.
引文
[1] Su FL,Li HD. Advance in search for pharmacokinetics of an antipressant: venlafaxine [J]. Chin J Clin Pharmacol, 2007, 23(3):223-226.
[2] Bauer M, Tharmanathan P, Volz HP, et al. The effect of Venlafaxine compared with other antidepressants and placebo in the treatment of major depression [J].Eur Arch Psychiatry Clin Neurosci. 2009,259:172-185.
[3] Fogelman SM, Schmider J, Venkatakrishnan K, et al. O- and N-demethylation of Venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants [J]. Neuropsychopharmacology, 1999, 20(5):480-490.
[4] Mcalpine DE, Biernacka JM, Mrazek DA, et al. Effect of cytochrome P450 enzyme polymorphisms on pharmacokinetics of lafaxine [J]. Ther Drug Monit, 2011, 33(1):14-20.
[5] Wei LJ, Yao ZJ. Research progress on the relationship between CYP2D6 gene polymorphism and the antidepressive effects of Venlafaxine [J]. Chin J Psychiatry, 2015, 48(2):118-121.
[6] McAlpine DE, Biernacka JM, Mrazek DA, et al. Effect of cytochrome P450 enzyme polymorphisms on pharmacokinetics of Venlafaxine [J].Ther Drug Monit, 2011. 33(1):14-20.
[7] http://www.internationalgenome.org/
[8] Nichols A I, Lobello K, Guico-Pabia C J, et al. Venlafaxine metabolism as a marker of cytochrome P450 enzyme 2D6 metabolizer status [J]. J Clin Psychopharmacol, 2009, 29(4):383.
[9] Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant Venlafaxine [J]. J Clin Pharm Ther, 2006, 31(5):493-502.
[10] Franconi F, Brunelleschi S, Steardo L, et al. Gender differences in drug responses [J]. Pharmacol Res, 2007, 55(2):81-95.
[2] Bauer M, Tharmanathan P, Volz HP, et al. The effect of Venlafaxine compared with other antidepressants and placebo in the treatment of major depression [J].Eur Arch Psychiatry Clin Neurosci. 2009,259:172-185.
[3] Fogelman SM, Schmider J, Venkatakrishnan K, et al. O- and N-demethylation of Venlafaxine in vitro by human liver microsomes and by microsomes from cDNA-transfected cells: effect of metabolic inhibitors and SSRI antidepressants [J]. Neuropsychopharmacology, 1999, 20(5):480-490.
[4] Mcalpine DE, Biernacka JM, Mrazek DA, et al. Effect of cytochrome P450 enzyme polymorphisms on pharmacokinetics of lafaxine [J]. Ther Drug Monit, 2011, 33(1):14-20.
[5] Wei LJ, Yao ZJ. Research progress on the relationship between CYP2D6 gene polymorphism and the antidepressive effects of Venlafaxine [J]. Chin J Psychiatry, 2015, 48(2):118-121.
[6] McAlpine DE, Biernacka JM, Mrazek DA, et al. Effect of cytochrome P450 enzyme polymorphisms on pharmacokinetics of Venlafaxine [J].Ther Drug Monit, 2011. 33(1):14-20.
[7] http://www.internationalgenome.org/
[8] Nichols A I, Lobello K, Guico-Pabia C J, et al. Venlafaxine metabolism as a marker of cytochrome P450 enzyme 2D6 metabolizer status [J]. J Clin Psychopharmacol, 2009, 29(4):383.
[9] Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant Venlafaxine [J]. J Clin Pharm Ther, 2006, 31(5):493-502.
[10] Franconi F, Brunelleschi S, Steardo L, et al. Gender differences in drug responses [J]. Pharmacol Res, 2007, 55(2):81-95.