Bergstrom R F, Goldberg M J, Cerimele B J, Hatcher B L
Eli Lilly and Company, Lilly Research Laboratories, Wishard Memorial Hospital, Indianapolis, IN 46202, USA.
Clin Pharmacol Ther. 1997 Dec;62(6):643-51. doi: 10.1016/S0009-9236(97)90084-9.
To assess whether fluoxetine and its metabolite, norfluoxetine, are inhibitors of the metabolism of CYP3A substrates.
Because inhibition of the first-pass metabolism of terfenadine may be associated with fatal arrhythmia, we assessed the possibility that fluoxetine inhibits this metabolism as a model for CYP3A drug interactions.
Male subjects (n = 12) were given two single doses of 60 mg terfenadine alone (treatment 1) and again after the eighth dose in a 9-day regimen of 60 mg fluoxetine once a day (treatment 2). Blood samples, collected up to 48 hours after each terfenadine dose, were assayed for terfenadine and terfenadine acid metabolite. The assay limits of quantification were 0.1 ng/ml and 5.0 ng/ml, respectively. Noncompartmental pharmacokinetic data for terfenadine and terfenadine acid metabolite were compared between treatments.
Mean value +/- SD plasma concentrations of fluoxetine (165 +/- 45 ng/ml) and norfluoxetine (83 +/- 23 ng/ml) achieved after the eighth dose did not cause a significant change in terfenadine acid metabolite pharmacokinetics. All terfenadine concentrations were less than 5 ng/ml and they were approximately 30% lower after fluoxetine pretreatment compared with terfenadine alone. The area under the concentration-time curve for terfenadine was lower after fluoxetine administration, a statistically significant difference, but the peak concentration of terfenadine was not significantly different. Because most antihistaminic activity after terfenadine administration is attributed to its acid metabolite, the small decrease in terfenadine concentration is not clinically significant. No subject discontinued the drugs because of an adverse event.
Fluoxetine did not inhibit the metabolism of terfenadine and is unlikely to affect the metabolism of terfenadine or other drugs that are CYP3A substrates.
评估氟西汀及其代谢产物去甲氟西汀是否为细胞色素P450 3A（CYP3A）底物代谢的抑制剂。
由于特非那定首过代谢的抑制可能与致命性心律失常有关，我们评估了氟西汀抑制这种代谢作为CYP3A药物相互作用模型的可能性。
男性受试者（n = 12）单次服用60 mg特非那定（治疗1），之后在为期9天、每天服用60 mg氟西汀的方案中，于第8剂后再次服用60 mg特非那定（治疗2）。在每次服用特非那定后长达48小时采集血样，检测特非那定及其酸性代谢产物。定量分析下限分别为0.1 ng/ml和5.0 ng/ml。比较两种治疗中特非那定及其酸性代谢产物的非房室药代动力学数据。
第8剂后达到的氟西汀（165±45 ng/ml）和去甲氟西汀（83±23 ng/ml）的血浆浓度平均值±标准差未导致特非那定酸性代谢产物药代动力学的显著变化。所有特非那定浓度均低于5 ng/ml，与单独服用特非那定相比，氟西汀预处理后浓度约低30%。氟西汀给药后特非那定的浓度-时间曲线下面积较低，具有统计学显著差异，但特非那定的峰浓度无显著差异。由于服用特非那定后的大多数抗组胺活性归因于其酸性代谢产物，特非那定浓度的小幅下降在临床上无显著意义。没有受试者因不良事件而停药。
氟西汀不抑制特非那定的代谢，不太可能影响特非那定或其他CYP3A底物药物的代谢。
