Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
INSERM UMR-S1144, Paris, France.
J Clin Psychiatry. 2018 Mar/Apr;79(2). doi: 10.4088/JCP.16m11387.
Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach.
From January 2015 to August 2015, 64 patients on a stable antidepressant regimen underwent a simultaneous assessment of steady-state antidepressant concentration and DME (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A) and P-glycoprotein transporter activity using a cocktail phenotyping approach. Psychiatric diagnoses were in accordance with DSM-5.
We observed a high proportion of subjects (> 20%) with reduced activity of CYP2C19, CYP2D6, CYP3A4, and P-glycoprotein. As expected, higher CYP activity for major metabolic pathways was associated with lower concentration of the parent compound (CYP2C19 and escitalopram, P = .025; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .001), higher concentration of the metabolite (CYP2D6 and O-desmethylvenlafaxine, P = .007), and higher metabolite-to-parent drug ratio (CYP2C19 and escitalopram, P = .03; CYP2D6 and fluoxetine, P < .001; CYP2C19 and sertraline, P = .048; CYP2B6 and sertraline, P = .006). Phenotyping also highlighted the relevance of a minor metabolic pathway for venlafaxine (CYP3A4). Insufficient response and adverse reactions to antidepressants were not significantly associated with plasma antidepressant concentration, DME, or P-glycoprotein activity. Tolerance of the phenotypic test in ambulatory settings was found to be excellent.
The phenotypic assessment of DMEs and a transporter is a valuable, well-tolerated method to explore the interindividual variability in drug disposition in clinical settings. The method is able to account for the inhibitory activity of antidepressants themselves and for polymedication, which is frequent in this population of refractory depressed patients.
ClinicalTrials.gov identifier: NCT02438072.
药物代谢酶（DME），如细胞色素 P450（CYP）酶和转运体，已成为药物代谢和反应变异性的主要决定因素。本研究在门诊临床环境中调查了 CYP 和 P-糖蛋白活性与血浆抗抑郁药浓度之间的关系。次要结局为抗抑郁疗效和耐受性。我们还描述了接受抗抑郁治疗的患者的表型，并评估了微创表型分析方法的耐受性。
从 2015 年 1 月至 2015 年 8 月，64 名接受稳定抗抑郁治疗方案的患者同时使用鸡尾酒表型分析方法评估稳态抗抑郁药浓度和 DME（CYP1A2、CYP2B6、CYP2C9、CYP2C19、CYP2D6、CYP3A）和 P-糖蛋白转运体活性。精神科诊断符合 DSM-5 标准。
我们观察到超过 20%的患者 CYP2C19、CYP2D6、CYP3A4 和 P-糖蛋白的活性降低。正如预期的那样，主要代谢途径的 CYP 活性越高，母体化合物的浓度越低（CYP2C19 和依他普仑，P =.025；CYP2D6 和氟西汀，P <.001；CYP2C19 和舍曲林，P =.001），代谢产物的浓度越高（CYP2D6 和 O-去甲文拉法辛，P =.007），代谢产物与母体药物的比值越高（CYP2C19 和依他普仑，P =.03；CYP2D6 和氟西汀，P <.001；CYP2C19 和舍曲林，P =.048；CYP2B6 和舍曲林，P =.006）。表型分析还突出了文拉法辛（CYP3A4）次要代谢途径的相关性。抗抑郁药反应不足和不良反应与血浆抗抑郁药浓度、DME 或 P-糖蛋白活性无显著相关性。在门诊环境中，表型测试的耐受性被发现很好。
DME 和转运体的表型评估是一种有价值的、耐受性良好的方法，可在临床环境中探索药物处置的个体间变异性。该方法能够解释抗抑郁药本身的抑制活性和该难治性抑郁患者人群中常见的多药治疗。
ClinicalTrials.gov 标识符：NCT02438072。
