Lane R M
Pfizer, Inc., New York, NY 10017, USA.
Int Clin Psychopharmacol. 1996 Dec;11 Suppl 5:31-61. doi: 10.1097/00004850-199612005-00005.
Obsessive-compulsive disorder (OCD) is a chronic disorder requiring long-term treatment. The pharmacological management of the disorder, therefore, requires the use of agents which, in addition to being efficacious and well tolerated, are unlikely to cause pharmacokinetic drug-drug interactions with concomitantly administered medication which the patient is receiving or may receive in the future. The selective serotonin reuptake inhibitors (SSRIs) have similar pharmacodynamic profiles but their pharmacokinetic profiles are very different. Perhaps the most substantial pharmacokinetic difference among these drugs is in their potential for drug-drug interactions via the inhibition of cytochrome P450 (CYP) isoenzymes. This review provides comprehensive background information on these enzyme systems and discusses their significance with respect to the optimal care of patients. Fluoxetine is a substantial inhibitor of CYP2D6, has mild effects on CYP3A3/4, and may also have effects on CYP2C9/10 and CYP2C19. Effects on drugs metabolized by these enzymes can persist for many weeks after fluxoetine discontinuation due to the long half-life of fluoxetine and its active metabolite norfluoxetine. Fluvoxamine is a substantial inhibitor of CYP1A2 and CYP2C19, and a moderate inhibitor of CYP3A3/4. Paroxetine is a substantial inhibitor of CYP2D6. In contrast, sertraline and citalopram are mild inhibitors of CYP2D6 at their usually effective doses and are not known to produce clinically meaningful inhibition of any other isoenzymes. However, citalopram has not been well studied against all of these enzymes, especially in vivo. An increased risk of pharmacokinetic drug interactions is the immediate clinical consequence of the inhibitory effects of these drugs on CYP isoenzymes. However, with the emphasis on long-term treatment, particularly in chronic conditions such as OCD, it will also be important to determine the long-term clinical consequences of substantially inhibiting specific CYP isoenzymes with those SSRIs which have these effects. Thus knowledge of the substrates and inhibitors of CYP isoenzymes may help clinicians to anticipate and avoid pharmacokinetic drug interactions and may better define rational prescribing practices.
强迫症（OCD）是一种需要长期治疗的慢性疾病。因此，该疾病的药物治疗需要使用除了有效且耐受性良好之外，不太可能与患者正在服用或未来可能服用的同时给药药物发生药代动力学药物相互作用的药物。选择性5-羟色胺再摄取抑制剂（SSRIs）具有相似的药效学特征，但它们的药代动力学特征却大不相同。这些药物之间最显著的药代动力学差异可能在于它们通过抑制细胞色素P450（CYP）同工酶而产生药物相互作用的可能性。本综述提供了关于这些酶系统的全面背景信息，并讨论了它们对于患者最佳治疗的意义。氟西汀是CYP2D6的强效抑制剂，对CYP3A3/4有轻微影响，也可能对CYP2C9/10和CYP2C19有影响。由于氟西汀及其活性代谢产物去甲氟西汀的半衰期较长，这些酶对药物代谢的影响在氟西汀停药后可能会持续数周。氟伏沙明是CYP1A2和CYP2C19的强效抑制剂，以及CYP3A3/4的中度抑制剂。帕罗西汀是CYP2D6的强效抑制剂。相比之下，舍曲林和西酞普兰在其通常有效剂量下是CYP2D6的轻度抑制剂，并且尚未发现对任何其他同工酶产生具有临床意义的抑制作用。然而，西酞普兰尚未针对所有这些酶进行充分研究，尤其是在体内。这些药物对CYP同工酶的抑制作用的直接临床后果是药代动力学药物相互作用风险增加。然而，鉴于强调长期治疗，特别是在诸如强迫症这样的慢性疾病中，确定那些具有这些作用的SSRIs对特定CYP同工酶的显著抑制作用的长期临床后果也将很重要。因此，了解CYP同工酶的底物和抑制剂可能有助于临床医生预测和避免药代动力学药物相互作用，并可能更好地确定合理的处方实践。
