ASSESSMENT OF THE POTENTIAL FOR A PHARMACOKINETIC INTERACTION BETWEENFLUOXETINE AND TERFENADINE

Objective: To assess whether fluoxetine and its metabolite, norfluoxet ine, are inhibitors of the metabolism of CYP3A substrates. Background: Because inhibition of the first-pass metabolism of terfenadine may be associated with fatal arrhythmia, we assessed the possibility that fl uoxetine inhibits this metabolism as a model for CYP3A drug interactio ns. Methods: 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 sa mples, collected up to 48 hours after each terfenadine dose, were assa yed for terfenadine and terfenadine acid metabolite. The assay limits of quantification were 0.1 ng/ml and 5.0 ng/ml, respectively. Noncompa rtmental pharmacokinetic data for terfenadine and terfenadine acid met abolite were compared between treatments. Results: Mean value +/- SD p lasma concentrations of fluoxetine (165 +/- 45 ng/ml) and norfluoxetin e (83 +/- 23 ng/ml) achieved after the eighth dose did not cause a sig nificant change in terfenadine acid metabolite pharmacokinetics. All t erfenadine concentrations were less than 5 ng/ml and they were approxi mately 30% lower after fluoxetine pretreatment compared with terfenadi ne 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 signifi cantly different. Because most antihistaminic activity after terfenadi ne administration is attributed to its acid metabolite, the small decr ease in terfenadine concentration is not clinically significant. No su bject discontinued the drugs because of an adverse event. Conclusion: Fluoxetine did not inhibit the metabolism of terfenadine and is unlike ly to affect the metabolism of terfenadine or other drugs that are CYP 3A substrates.