Greenblatt D J, Preskorn S H, Cotreau M M, Horst W D, Harmatz J S
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111.
Clin Pharmacol Ther. 1992 Nov;52(5):479-86. doi: 10.1038/clpt.1992.175.
Volunteer male subjects received single 1.0 mg oral doses of alprazolam and of clonazepam on two occasions, during coadministration of 40 mg/day fluoxetine or of placebo. When the sequence of trials was placebo first and fluoxetine second, fluoxetine coadministration significantly prolonged alprazolam half-life (20 versus 17 hours) and reduced clearance (48 versus 61 ml/min). No effect of fluoxetine was seen when fluoxetine was given first and placebo second, because norfluoxetine persisted into the placebo phase even though fluoxetine had been discontinued 2 weeks earlier. Fluoxetine had no significant effects on clonazepam elimination half-life or clearance regardless of the sequence of fluoxetine and placebo administration. In the fluoxetine-placebo sequence, fluoxetine significantly increased the rate of clonazepam absorption. Thus fluoxetine appears to impair clearance of alprazolam by way of microsomal oxidation but does not alter clearance of clonazepam by way of nitroreduction. The very slow elimination of norfluoxetine should be considered in the design of clinical or pharmacokinetic studies that involve fluoxetine.
男性志愿者在分别服用40毫克/天氟西汀或安慰剂的同时，分两次口服单剂量1.0毫克阿普唑仑和氯硝西泮。当试验顺序为先服用安慰剂后服用氟西汀时，氟西汀的合用显著延长了阿普唑仑的半衰期（20小时对17小时）并降低了清除率（48毫升/分钟对61毫升/分钟）。当先服用氟西汀后服用安慰剂时，未观察到氟西汀的影响，因为尽管氟西汀在2周前已停药，但去甲氟西汀持续到了安慰剂阶段。无论氟西汀和安慰剂的给药顺序如何，氟西汀对氯硝西泮的消除半衰期或清除率均无显著影响。在氟西汀-安慰剂顺序中，氟西汀显著提高了氯硝西泮的吸收速率。因此，氟西汀似乎通过微粒体氧化损害了阿普唑仑的清除，但并未通过硝基还原改变氯硝西泮的清除。在涉及氟西汀的临床或药代动力学研究设计中，应考虑去甲氟西汀的消除非常缓慢这一因素。
