Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients with Depression
Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients with Depression
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CYP2D6 基因型对日本抑郁症精神病患者文拉法辛代谢的影响
DOI：
10.1097/ftd.0000000000000854
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发表时间：
2020
影响因子：
2.5
通讯作者：
Shimoda Kazutaka
中科院分区：
文献类型：
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作者：
Komahashi-Sasaki Hazuki;Yasui-Furukori Norio;Sasaki Taro;Shinozaki Masataka;Hayashi Yuki;Kato Kazuko;Inoue Yoshimasa;Tsuchimine Shoko;Watanabe Takashi;Sugawara Norio;Shimoda Kazutaka
背景：文拉法辛(VEN)主要由CYP2D6代谢。尽管已有几项研究报道了CYP2D6对VEN和O-去甲基文拉法辛(ODV)在白人体内的药代动力学的显著影响，但关于亚洲特有的CYP2D6基因对VEN代谢的影响的数据有限。本研究评估了日本患者中CYP2D6*10和CYP2D6*5基因对稳态血浆VEN和ODV浓度的影响。方法：75例接受VEN治疗的日本抑郁症患者。用高效液相色谱法测定稳态血浆中VEN和ODV的浓度。聚合酶链式反应检测细胞色素P4502D6基因分型。用逐步多元回归分析自变量(性别、年龄、吸烟习惯、突变等位基因数目)、因变量(校正后的剂量和体重)、因变量(校正后的剂量和体重)和剂量/体重之间的关系。结果：经体重校正后的VEN日剂量与血浆VEN(r=0.498，P<0.001)和ODV(r=0.380，P=0.001)呈正相关；ODV血浆浓度约为VEN血浆浓度的3.2倍(VEN对ODV分别为18.60 ng/mL和59.10 ng/mL)。VEN血浆浓度(经剂量和体重校正后)与不同数目的CYP2D6突变等位基因没有差异。但随着突变等位基因数目的增加，ODV/VEN比值降低(P=0.001)。结论：这是首次在临床环境中检验该基因的作用。虽然没有观察到对VEN或ODV血浆浓度的影响，但CYP2D6基因多态性会影响ODV/VEN比值。需要进一步的研究来确认这些发现的临床相关性。
Background:Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6* 10 and CYP2D6* 5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients.Methods:This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6* 10 and CYP2D6* 5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio.Results:Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r= 0.498, P< 0.001) and ODV (r= 0.380, P= 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV= 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P= 0.001).Conclusions:This is the first study to examine the effects of CYP2D6* 10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.BACKGROUND