Pharmacokinetics of Citalopram in Relation to the Sparteine and the Mephenytoin Oxidation Polymorphisms
Pharmacokinetics of Citalopram in Relation to the Sparteine and the Mephenytoin Oxidation Polymorphisms
复制标题
西酞普兰与金雀花碱和美芬妥英氧化多态性相关的药代动力学
作者：
S. H. Sindrup;K. Brøsen;M. G. Hansen;T. Aaes;K. Overø;L. Gram
在24名健康男性志愿者中研究了选择性5-羟色胺再摄取抑制剂西酞普兰的代谢与鹰爪豆碱和美芬妥英氧化多态性之间的关系，这些志愿者包括鹰爪豆碱和美芬妥英的快代谢者（n = 10）、鹰爪豆碱的慢代谢者（n = 8）和美芬妥英的慢代谢者（n = 6）。每例受试者接受40 mg/天西酞普兰治疗10天，并在血清和尿液中测定西酞普兰及其脱甲基代谢物和去二甲基代谢物。使用非对映体选择性分析方法（高效液相色谱法），结果表明，西酞普兰消除部分取决于美芬妥英加氧酶，因为西酞普兰的稳态血清浓度、半衰期和血清浓度/时间曲线下面积在美芬妥英弱代谢者中显著高于美芬妥英快代谢者。与快代谢者相比，美芬妥英弱代谢者的西酞普兰总清除率和去甲基化清除率（形成去甲基西酞普兰）均显著较低（中位数分别为15.2 vs. 27.3和2.6 vs. 5.9 L/h）。进一步表明，去甲基西酞普兰去甲基化为去二甲基西酞普兰依赖于金雀花碱加氧酶CYP 2D 6。去二甲基西酞普兰几乎不能检测到任何弱代谢的金雀花碱，对比可测量的血清水平在所有金雀花碱/美芬妥英快代谢。与快代谢者相比，鹰爪豆碱弱代谢者中去甲基西酞普兰的去甲基化清除率显著较低（分别为0.3 vs 2.4 L/h）。在西酞普兰给药期间，在金雀花碱的快代谢者中，金雀花碱代谢比从中位数0.31适度增加到0.80，而美芬妥英S/R比在西酞普兰治疗期间没有改变。因此，鹰爪豆碱和美芬妥英氧化多态性似乎对西酞普兰的总药代动力学变异性有部分贡献。
The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.