Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone
Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone
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DOI：
10.1177/0091270003251864
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发表时间：
2003-04-01
影响因子：
2.9
通讯作者：
Shader, RI
中科院分区：
文献类型：
--
作者：
Greenblatt, DJ;von Moltke, LL;Shader, RI
抗逆转录病毒药物可能参与影响其他抗逆转录病毒药物的功效和毒性的药物相互作用，以及同时发生或并发疾病的药物治疗。病毒蛋白酶抑制剂利托那韦可能通过抑制细胞色素 P450-3A (CYP3A) 亚型的活性而引起药物相互作用。在一项单剂量、盲法、四向交叉研究中，10 名健康志愿者受试者接受 50 毫克盐酸曲唑酮或匹配安慰剂，同时服用低剂量利托那韦（四剂，每剂 200 毫克）或安慰剂。与对照条件相比，利托那韦显着降低曲唑酮的表观口服清除率（155 +/- 23 vs. 75 +/- 12 ml/min，p < 0.001），延长消除半衰期（6.7 +/- 0.7 vs. 14.9 +/- 3.9 h，p < 0.05），并增加血浆峰浓度（842 +/- 64 vs. 1125 +/-） 111 ng/ml，p < 0.05）（平均值 +/- SE）。与曲唑酮加安慰剂相比，曲唑酮与利托那韦联合用药会增加镇静、疲劳和表现障碍；差异仅在数字符号替换测试中达到显着性。当曲唑酮与利托那韦联合使用时，三名受试者出现恶心、头晕或低血压；其中 1 名受试者还经历了晕厥，因此短期低剂量利托那韦给药会损害曲唑酮的口服清除率并增加不良反应的发生。这些发现与利托那韦对 CYP3A 介导的曲唑酮代谢的损害一致。
Antiretroviral agents may participate in drug interactions that influence the efficacy and toxicity of other antiretrovirals, as well as pharmacologic treatments of coincident or complicating diseases. The viral protease inhibitor, ritonavir, may cause drug interactions by inhibiting the activity of cytochrome P450-3A (CYP3A) isoforms. In a single-dose, blinded, four-way crossover study, 10 healthy volunteer subjects received 50 mg of trazodone hydrochloride or matching placebo concurrent with low-dose ritonavir (four doses of 200 mg each) or with placebo. Compared to the control condition, ritonavir significantly reduced apparent oral clearance of trazodone (155 +/- 23 vs. 75 +/- 12 ml/min, p < 0.001), prolonged elimination half-life (6.7 +/- 0.7 vs. 14.9 +/- 3.9 h, p < 0.05), and increased peak plasma concentrations (842 +/- 64 vs. 1125 +/- 111 ng/ml, p < 0.05) (mean +/- SE). Coadministration of trazodone with ritonavir increased sedation, fatigue, and performance impairment compared to trazodone plus placebo; differences reached significance only for the digit-symbol substitution test. Three subjects experienced nausea, dizziness, or hypotension when trazodone was given with ritonavir; 1 of these subjects also experienced syncope, Thus short-term low-dose administration of ritonavir impairs oral clearance of trazodone and increases the occurrence of adverse reactions. The findings are consistent with impairment of CYP3A-mediated trazodone metabolism by ritonavir.