Rf. Bergstrom et al., ASSESSMENT OF THE POTENTIAL FOR A PHARMACOKINETIC INTERACTION BETWEENFLUOXETINE AND TERFENADINE, Clinical pharmacology and therapeutics, 62(6), 1997, pp. 643-651
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.