Sproule Beth A, Hazra Monica, Pollock Bruce G
The Centre for Addiction and Mental Health, University of Toronto, Canada.
Drugs Today (Barc). 2008 Jul;44(7):475-87. doi: 10.1358/dot.2008.44.7.1227147.
Desvenlafaxine (O-desmethylvenlafaxine) is the major active metabolite of venlafaxine. Desvenlafaxine succinate is now undergoing active evaluation for its therapeutic efficacy in a variety of disorders, including major depressive disorder, vasomotor symptoms associated with menopause, fibromyalgia and diabetic neuropathy. Desvenlafaxine is a serotonin and norepinephrine reuptake inhibitor (SNRI) with similar activity to its parent compound venlafaxine, and little affinity for other brain targets, including muscarinic, cholinergic, histamine H(1) and alpha-adrenergic receptors. Desvenlafaxine has linear pharmacokinetics, low protein binding, a half-life of approximately 10 hours and is metabolized primarily via glucuronidation, and to a minor extent through CYP3A4. The desvenlafaxine succinate formulation appears to have good oral bioavailability. Clearance rates are reduced in the elderly, those with severe renal dysfunction and those with moderate to severe hepatic dysfunction, which may require dosage adjustments. Three published clinical trials have shown supportive but mixed results for the efficacy of desvenlafaxine in the treatment of major depressive disorder with daily doses ranging from 100 mg to 400 mg. One published clinical trial has shown mixed results for the efficacy of desvenlafaxine in the treatment of vasomotor symptoms associated with menopause with daily doses ranging from 50 mg to 200 mg. In these four clinical trials, desvenlafaxine was associated with several mild adverse effects, with the most common effect being nausea. Less common, but more serious, adverse effects reported in these trials included hypertension, QTc interval prolongation, exacerbation of ischemic cardiac disease, elevated lipids and elevated liver enzymes. The exact nature of these serious adverse effects, including the prevalence, clinical significance and potential risk factors, still needs to be fully elucidated. Desvenlafaxine has a low propensity for pharmacokinetic-based drug interactions, although it has the same potential for pharmacodynamic interactions as other serotonin-norepinephrine reuptake inhibitors. Desvenlafaxine is currently another treatment option for major depressive disorder. The only identified potential advantage of desvenlafaxine over venlafaxine or other antidepressant agents at this time is the apparently reduced risk for pharmacokinetic drug interactions.
去甲文拉法辛（O-去甲基文拉法辛）是文拉法辛的主要活性代谢产物。琥珀酸去甲文拉法辛目前正在接受积极评估，以确定其在多种疾病中的治疗效果，包括重度抑郁症、与更年期相关的血管舒缩症状、纤维肌痛和糖尿病性神经病变。去甲文拉法辛是一种5-羟色胺和去甲肾上腺素再摄取抑制剂（SNRI），与其母体化合物文拉法辛具有相似的活性，对其他脑靶点（包括毒蕈碱、胆碱能、组胺H(1)和α-肾上腺素能受体）的亲和力较低。去甲文拉法辛具有线性药代动力学、低蛋白结合率、约10小时的半衰期，主要通过葡萄糖醛酸化代谢，在较小程度上通过CYP3A4代谢。琥珀酸去甲文拉法辛制剂似乎具有良好的口服生物利用度。老年人、严重肾功能不全者和中度至重度肝功能不全者的清除率降低，可能需要调整剂量。三项已发表的临床试验表明，去甲文拉法辛治疗重度抑郁症的疗效有支持性但结果不一，日剂量范围为100毫克至400毫克。一项已发表的临床试验表明，去甲文拉法辛治疗与更年期相关的血管舒缩症状的疗效结果不一，日剂量范围为50毫克至200毫克。在这四项临床试验中，去甲文拉法辛与几种轻度不良反应相关，最常见的是恶心。这些试验中报告的较不常见但更严重的不良反应包括高血压、QTc间期延长、缺血性心脏病加重、血脂升高和肝酶升高。这些严重不良反应的确切性质，包括患病率、临床意义和潜在风险因素，仍需充分阐明。去甲文拉法辛基于药代动力学的药物相互作用倾向较低，尽管它与其他5-羟色胺-去甲肾上腺素再摄取抑制剂具有相同的药效学相互作用可能性。去甲文拉法辛目前是重度抑郁症的另一种治疗选择。目前确定的去甲文拉法辛相对于文拉法辛或其他抗抑郁药的唯一潜在优势是药代动力学药物相互作用的风险明显降低。
