Newer antidepressants and the cytochrome P450 system.
Newer antidepressants and the cytochrome P450 system.
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DOI：
10.1176/ajp.153.3.311
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发表时间：
1996-03
期刊：
影响因子：
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通讯作者：
C. Nemeroff;C. DeVane;B. Pollock
中科院分区：
文献类型：
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作者：
C. Nemeroff;C. DeVane;B. Pollock
目的评价新型抗抑郁药对细胞色素P450酶抑制作用的体内外证据，为临床避免和管理药物相互作用提供建议。方法对1966 ~ 1995年国际上有关细胞色素P450系统及其药物相互作用的文献进行综述。评估了体外研究、人类受试者的药代动力学试验和病例报告。结果：新的抗抑郁药各自抑制不同的细胞色素P450酶簇，这与药物相互作用的可能性有关。细胞色素P450 1A 2被氟伏沙明抑制，并与茶碱、氯氮平等药物相互作用有关。氟西汀、去甲氟西汀、舍曲林和帕罗西汀是细胞色素P450 2D 6的有效体外抑制剂，能够引起血浆地昔帕明和去甲替林浓度显著升高。氟西汀、舍曲林和氟伏沙明被认为抑制细胞色素P450 2C，因为观察到与苯妥英、地西泮和其他由这些酶代谢的药物的相互作用。细胞色素P450 3A 4代谢特非那定、阿司咪唑、卡马西平、阿普唑仑、三唑仑和其他苯二氮卓类药物。当这些药物与氟伏沙明、奈法唑酮、氟西汀和舍曲林联合给药时，其血浆浓度升高。结论：大多数新型抗抑郁药与临床显著药物相互作用的风险相关。快速增长的文献为细胞色素P450抑制和个体抗抑郁药药物相互作用风险的不同特征提供了证据。这些发现强调了需要明确的体内相互作用研究的表型患者的血浆与临床有效剂量的抗抑郁药治疗，直接比较的临床研究，并在临床实践中的表型的效用评估的研究。
OBJECTIVE This review evaluates the in vitro and in vivo evidence for inhibition of cytochrome P450 enzymes by the newer antidepressants and provides clinical recommendations for avoiding and managing drug interactions. METHOD The international literature on the cytochrome P450 system and related drug interactions from 1966 to 1995 was reviewed. In vitro studies, pharmacokinetic trials in human subjects, and case reports were assessed. RESULTS The newer antidepressants each inhibit a different cluster of cytochrome P450 enzymes, which are of relevance to the potential for drug interactions. Cytochrome P450 1A2 is inhibited by fluvoxamine and is implicated in drug interactions with theophylline, clozapine, and others. Fluoxetine, norfluoxetine, sertraline, and paroxetine are potent in vitro inhibitors of cytochrome P450 2D6 and are capable of causing marked elevations in plasma desipramine and nortriptyline concentrations. Fluoxetine, sertraline, and fluvoxamine are believed to inhibit cytochrome P450 2C because of observed interactions with phenytoin, diazepam, and other drugs metabolized by these enzymes. Cytochrome P450 3A4 metabolizes terfenadine, astemizole, carbamazepine, alprazolam, triazolam, and other benzodiazepines. Plasma concentrations of these drugs have increased when they are administered with fluvoxamine, nefazodone, fluoxetine, and sertraline. CONCLUSIONS The majority of the newer antidepressants are associated with a risk for clinically significant drug interactions. A rapidly growing body of literature provides evidence for a distinct profile of cytochrome P450 inhibition and drug interaction risks by individual antidepressants. These findings underscore the need for definitive in vivo interaction studies of plasma from phenotyped patients treated with clinically effective antidepressant doses of medication, for direct comparative clinical studies, and for studies assessing the utility of phenotyping in clinical practice.