Ball S E, Ahern D, Scatina J, Kao J
Drug Safety and Metabolism, Wyeth-Ayerst Research, Princeton, NJ 08543-8000, USA.
Br J Clin Pharmacol. 1997 Jun;43(6):619-26. doi: 10.1046/j.1365-2125.1997.00591.x.
In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450 s was also studied (CYP3A4, CYP2D6, CYP1A2).
Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6 beta-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively).
Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (Ki values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 microM, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (Ki of 24.7 +/- 8.9 microM). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a Ki of 1.3 +/- 0.5 microM. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (Ki of 41.0 +/- 9.5 microM) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (Ki values of 3.9 +/- 1.7 and 1.7 +/- 0.9 microM, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM.
It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.
为了预测具有潜在临床意义的药物相互作用，研究了新型抗抑郁药文拉法辛在人肝微粒体中抑制细胞色素P450 2D6（CYP2D6）介导的丙咪嗪和去甲丙咪嗪2-羟化反应的能力。将获得的数据与选择性5-羟色胺再摄取抑制剂氟西汀、舍曲林、氟伏沙明和帕罗西汀进行比较。还研究了文拉法辛抑制其他几种主要细胞色素P450酶（CYP3A4、CYP2D6、CYP1A2）的可能性。
通过人肝微粒体孵育中对照和抑制速率数据的狄克逊图，确定文拉法辛、帕罗西汀、氟西汀、氟伏沙明和舍曲林作为丙咪嗪和去甲丙咪嗪2-羟化反应抑制剂的抑制常数（Ki）值。同样地，确定丙咪嗪和去甲丙咪嗪对肝微粒体中CYP2D6介导的文拉法辛O-去甲基化反应的抑制作用。基于对探针底物活性的抑制作用（分别为睾酮6β-羟化反应、乙氧异羟肟酸O-脱烷基反应和甲苯磺丁脲4-羟化反应），确定文拉法辛对CYP3A4、CYP1A2和CYP2C9的半数抑制浓度（IC50）值。
氟西汀、帕罗西汀和氟伏沙明是丙咪嗪2-羟化酶活性的强效抑制剂（Ki值分别为1.6±0.8、3.2±0.8和8.0±4.3微摩尔；平均值±标准差，n =
3），而舍曲林的抑制作用较弱（Ki为24.7±8.9微摩尔）。氟西汀对去甲丙咪嗪2-羟化反应也有显著抑制作用，Ki为1.3±0.5微摩尔。与所研究的选择性5-羟色胺再摄取抑制剂相比，文拉法辛作为丙咪嗪2-羟化反应抑制剂的效力较弱（Ki为41.0±9.5微摩尔）。丙咪嗪和去甲丙咪嗪对CYP2D6介导的文拉法辛O-脱甲基酶活性有显著抑制作用（Ki值分别为3.9±1.7和1.7±0.9微摩尔）。在浓度高达1毫摩尔时，文拉法辛不抑制乙氧异羟肟酸O-脱烷基酶（CYP1A2）、甲苯磺丁脲4-羟化酶（CYP2C9）或睾酮6β-羟化酶（CYP3A4）的活性。
得出结论，与几种最广泛使用的选择性5-羟色胺再摄取抑制剂相比，文拉法辛抑制CYP2D6底物（如丙咪嗪和去甲丙咪嗪）代谢的可能性较低，并且对其他几种主要人肝细胞色素P450酶底物的代谢也有较低的抑制作用。
