Gram L F, Hansen M G, Sindrup S H, Brøsen K, Poulsen J H, Aaes-Jørgensen T, Overø K F
Department of Clinical Pharmacology, Odense University, Denmark.
Ther Drug Monit. 1993 Feb;15(1):18-24.
The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.
选取8名健康年轻男性志愿者（年龄20 - 31岁），分为三个小组，研究口服剂量为40mg/天、持续10天的选择性5-羟色胺再摄取抑制剂西酞普兰与以下三种药物的药代动力学相互作用：（1）左美丙嗪（单次口服剂量50mg），（2）丙咪嗪（单次口服剂量100mg），（3）锂盐（口服30mmol/天，持续5天）。所有志愿者均被归类为司巴丁和甲妥英的广泛代谢者。每位受试者均完成三个研究阶段，一个阶段仅服用西酞普兰，一个阶段仅服用上述三种药物中的一种，另一个阶段则将西酞普兰与相应的另一种药物联合服用。对于西酞普兰及其代谢产物，采用了一种非对映体选择性分析方法（高效液相色谱法）。仅发现了两种具有统计学意义的相互作用。首先，左美丙嗪使西酞普兰主要代谢产物去甲西酞普兰的初始稳态水平升高了10% - 20%。其次，西酞普兰使地昔帕明（丙咪嗪的主要代谢产物）的单剂量血清浓度/时间曲线下面积增加了约50%，并相应降低了随后形成的代谢产物2-羟基地昔帕明的水平。这些发现与最近的观察结果一致，即（1）去甲西酞普兰（生成双去甲西酞普兰）的去甲基化部分通过司巴丁/异喹胍氧化酶（CYP2D6）介导，而左美丙嗪是CYP2D6的强效抑制剂；（2）去甲西酞普兰对CYP2D6的亲和力比对地昔帕明略强，因此可能抑制同样作为CYP2D6底物的地昔帕明的羟基化。
