Assessment of the potential for a pharmacokinetic interaction between fluoxetine and terfenadine.
OBJECTIVE
To assess whether fluoxetine and its metabolite, norfluoxetine, 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 fluoxetine inhibits this metabolism as a model for CYP3A drug interactions.


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 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.


RESULTS
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.


CONCLUSIONS
Fluoxetine did not inhibit the metabolism of terfenadine and is unlikely to affect the metabolism of terfenadine or other drugs that are CYP3A substrates.
Bergstrom
R F
RF
Eli Lilly and Company, Lilly Research Laboratories, Wishard Memorial Hospital, Indianapolis, IN 46202, USA.
Goldberg
M J
MJ
Cerimele
B J
BJ
Hatcher
B L
BL
D019540:Area Under Curve; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D004347:Drug Interactions; D004562:Electrocardiography / Q000187:drug effects; D005473:Fluoxetine / Q000493:pharmacokinetics* / Q000494:pharmacology; D006207:Half-Life; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D017367:Selective Serotonin Reuptake Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D016593:Terfenadine / Q000493:pharmacokinetics* / Q000494:pharmacology
D005473:Fluoxetine; D006634:Histamine H1 Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; D016593:Terfenadine