选择性血清素再摄取抑制剂的药代动力学-药效学关系。
文章的细节
-
引用
复制到剪贴板 -
鲍曼P
选择性血清素再摄取抑制剂的药代动力学-药效学关系。
临床药典，1996 Dec;31(6):444-69。
- PubMed ID
-
8968657 (PubMed视图］
- 摘要
-
最近引入的抗抑郁药，选择性血清素再摄取抑制剂(SSRIs)[西酞普兰、氟西汀、氟伏沙明、帕罗西汀和舍曲林]，以其临床疗效、良好的耐受性和相对安全性而闻名。它们在化学结构、代谢和药代动力学性质上存在差异。这些化合物的治疗药物监测并没有被广泛使用，因为临床反应最小且不良反应最佳的血药浓度范围还没有明确定义。最近几乎所有用于定量测定血液中SSRIs及其代谢物的检测方法都是基于高效液相色谱法(HPLC)或气相色谱法(GC)分离SSRIs。西酞普兰和氟西汀已作为外消旋化合物引入。母化合物的对映体及其去甲基代谢产物在药理特征、代谢和药代动力学方面存在一定差异。现在已经有了在血液中分析它们的立体选择性色谱方法。关于目前可用的SSRIs，在抑郁症患者中没有明确的血浆浓度-临床疗效关系，也没有任何定义毒性浓度的阈值。这可能是由于它们毒性低，且使用剂量不出现严重不良反应。SSRIs与肝脏中细胞色素P450 (CYP)同工酶的定性和定量相互作用差异很大。 CYP2D6 is inhibited by SSRIs, in order of decreasing potency paroxetine, norfluoxetine, fluoxetine, sertraline, citalopram and fluvoxamine. This may have clinical consequences with some but not all SSRIs, when they are taken with tricyclic antidepressants. Except for citalopram and paroxetine, little is known about the enzymes which control the biotransformation of the SSRIs. There have been many reports on marked pharmacokinetic interactions between fluoxetine and tricyclic antidepressants. Fluoxetine has a stronger effect on their hydroxylation than on their demethylation. Interactions observed between fluoxetine and alprazolam, midazolam and carbamazepine seem to occur on the level of CYP3A. Fluvoxamine strongly inhibits the N-demethylation of some tricyclic antidepressants of the tertiary amine type and of clozapine. This may lead to adverse effects but augmentation with fluvoxamine can also improve response in very rapid metabolisers, as it increases the bioavailability of the comedication. Fluvoxamine inhibits with decreasing potency, CYP1A2, CYP2C19, CYP2D6 and CYP1A1, but it is also an inhibitor of CYP3A. Fluoxetine and fluvoxamine have shown to increase methadone plasma concentrations in dependent patients. Some authors warn about a combination of monoamine oxidase (MAO) inhibitors with SSRIs, as this could lead to a serotonergic syndrome. Studies with healthy volunteers suggest, however, that a combination of moclobemide and SSRIs, such as fluvoxamine, should not present serious risks in promoting a serotonin syndrome. A combination of moclobemide and fluvoxamine has successfully been used in refractory depression, but more studies are needed, including plasma-concentration monitoring, before this combined treatment can be recommended. Paroxetine is a substrate of CYP2D6, but other enzyme(s) could also be involved. Its pharmacokinetics are linear in poor metabolisers of sparteine, and non-linear in extensive metabolisers. Due to its potent CYP2D6 inhibiting properties, comedication with this SSRI can lead to an increase of tricyclic antidepressants in plasma, as shown with amitriptyline and trimipramine. CYP3A has been claimed to be involved in the biotransformation of sertraline to norsertraline. Clinical investigations (with desipramine) confirmed in vitro findings that CYP2D6 inhibition by sertraline is only moderate. (ABSTRACT TRUNCATED)
引用本文的药物库数据
- 药物酶
-
药物 酶 种类 生物 药理作用 行动 阿米替林 细胞色素P450 2D6 蛋白质 人类 未知的底物细节 西酞普兰 细胞色素P450 2D6 蛋白质 人类 未知的底物抑制剂细节 去郁敏 细胞色素P450 2D6 蛋白质 人类 未知的底物抑制剂细节 酞 细胞色素P450 2D6 蛋白质 人类 未知的底物抑制剂细节 氟伏沙明 细胞色素P450 1A2 蛋白质 人类 未知的底物抑制剂细节 氟伏沙明 细胞色素P450 2C19 蛋白质 人类 没有抑制剂细节 氟伏沙明 细胞色素P450 2D6 蛋白质 人类 未知的底物抑制剂细节 氟伏沙明 细胞色素P450 3A4 蛋白质 人类 未知的底物抑制剂细节 帕罗西汀 细胞色素P450 2D6 蛋白质 人类 未知的底物抑制剂细节 舍曲林 细胞色素P450 2D6 蛋白质 人类 未知的底物抑制剂细节 三甲丙咪嗪 细胞色素P450 2D6 蛋白质 人类 未知的底物细节