Eap C B, Bertel-Laubscher R, Zullino D, Amey M, Baumann P
Unité de Biochimie et Psychopharmacologie Clinique, Département Universitaire de Psychiatrie, Adulte, Hôpital de Cery, Prilly-Lausanne, Switzerland.
Pharmacopsychiatry. 2000 May;33(3):112-5. doi: 10.1055/s-2000-7975.
On three occasions, unusually high trough plasma concentrations of venlafaxine were measured in a patient phenotyped and genotyped as being an extensive CYP2D6 metabolizer and receiving 450 mg/day of venlafaxine and multiple comedications. Values of 1.54 and of 0.60 mg/l of venlafaxine and O-desmethylvenlafaxine, respectively, were determined in the first blood sample, giving an unusually high venlafaxine to O-desmethylvenlafaxine ratio. This suggests an impaired metabolism of venlafaxine to O-desmethylvenlafaxine, and is most likely due to metabolic interactions with mianserin (240 mg/day) and propranolol (40 mg/day). Concentration of (S)-venlafaxine measured in this blood sample was almost twice as high as (R)-venlafaxine ((S)/(R) ratio: 1.94). At the second blood sampling, after addition of thioridazine (260 mg/day), which is a strong CYP2D6 inhibitor, concentrations of venlafaxine were further increased (2.76 mg/l), and concentrations of O-desmethylvenlafaxine decreased (0.22 mg/l). A decrease of the (S)/(R)-venlafaxine ratio (-20%) suggests a possible stereoselectivity towards the (R)-enantiomer of the enzyme(s) involved in venlafaxine O-demethylation at these high venlafaxine concentrations. At the third blood sampling, after interruption of thioridazine, concentrations of venlafaxine and O-desmethylvenlafaxine were similar to those measured in the first blood sample. This case report shows the importance of performing studies on the effects of either genetically determined or acquired deficiency of metabolism on the kinetics of venlafaxine.
在三次检测中，一名经表型和基因分型为CYP2D6广泛代谢型的患者，每日服用450毫克文拉法辛并同时服用多种药物，其血浆中文拉法辛的谷浓度异常高。在第一份血样中，文拉法辛和O-去甲基文拉法辛的浓度分别测定为1.54毫克/升和0.60毫克/升，文拉法辛与O-去甲基文拉法辛的比值异常高。这表明文拉法辛向O-去甲基文拉法辛的代谢受损，很可能是由于与米安色林（每日240毫克）和普萘洛尔（每日40毫克）的代谢相互作用。在这份血样中测得的（S）-文拉法辛浓度几乎是（R）-文拉法辛的两倍（（S）/（R）比值：1.94）。在第二次血样采集时，加入了强效CYP2D6抑制剂硫利达嗪（每日260毫克）后，文拉法辛浓度进一步升高（2.76毫克/升），而O-去甲基文拉法辛浓度降低（0.22毫克/升）。（S）/（R）-文拉法辛比值下降（-20%）表明，在这些高文拉法辛浓度下，参与文拉法辛O-去甲基化的酶对（R）-对映体可能存在立体选择性。在第三次血样采集时，硫利达嗪停药后，文拉法辛和O-去甲基文拉法辛的浓度与第一次血样中测得的浓度相似。本病例报告显示了研究基因决定的或后天获得的代谢缺陷对文拉法辛动力学影响的重要性。
