Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu-machi, Shimotsuga.
Sakura La Mental Clinic, Utsunomiya, Tochigi; and.
Ther Drug Monit. 2021 Oct 1;43(5):681-687. doi: 10.1097/FTD.0000000000000854.
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 CYP2D610 and CYP2D65 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients.
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, CYP2D610 and CYP2D65), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio.
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).
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.
文拉法辛（VEN）主要通过 CYP2D6 代谢。尽管有几项研究报道了 CYP2D6 对白人患者文拉法辛和 O-去甲基文拉法辛（ODV）药代动力学的显著影响，但关于亚洲特异性 CYP2D6 基因型对文拉法辛代谢影响的数据有限。本研究评估了 CYP2D610 和 CYP2D65 基因型对日本患者文拉法辛和 ODV 稳态血浆浓度的影响。
本研究纳入了 75 例接受文拉法辛治疗的抑郁症日本患者。使用液相色谱法测定文拉法辛和 ODV 的稳态血浆浓度。聚合酶链反应用于确定 CYP2D6 基因型。采用逐步多元回归分析，分析独立变量（性别、年龄、吸烟习惯和突变等位基因数、CYP2D610 和 CYP2D65）、受试者相关变量（文拉法辛和 ODV 的血浆浓度[均校正剂量和体重]）与 ODV/VEN 比值之间的关系。
文拉法辛（校正体重）的日剂量与文拉法辛（r = 0.498，P < 0.001）和 ODV（r = 0.380，P = 0.001）的血浆浓度呈显著相关；ODV 血浆浓度约为文拉法辛血浆浓度的 3.2 倍（文拉法辛与 ODV=18.60ng/mL 比 59.10ng/mL）。文拉法辛的血浆浓度（校正剂量和体重）与 CYP2D6 突变等位基因的数量无关。然而，随着 CYP2D6 突变等位基因数量的增加，ODV/VEN 比值降低（P = 0.001）。
这是首次在临床环境中研究 CYP2D6*10 的影响。尽管文拉法辛或 ODV 的血浆浓度没有受到影响，但 CYP2D6 多态性影响 ODV/VEN 比值。需要进一步研究来证实这些发现的临床意义。
