TERFENADINE-ANTIDEPRESSANT INTERACTIONS - AN IN-VITRO INHIBITION STUDY USING HUMAN LIVER-MICROSOMES

Aims Inhibition of the metabolism of terfenadine has been associated w ith torsades de Pointes ventricular arrhythmias. The aim of this study was to assess in vitro the potency of the antidepressants nefazodone, sertraline and fluoxetine in inhibiting terfenadine biotransformation . Methods Human liver microsomes were incubated with terfenadine and t he antidepressants at various concentrations. Formation of the two maj or metabolites of terfenadine was determined by h.p.l.c. Results The a pparent K-m for microsomes from four human livers was 11 +/- 5 and 18 +/- 3 mu M (mean +/- s.e. mean) for the N-dealkylation and C-hydroxyla tion pathways, respectively. Nefazodone, sertraline and fluoxetine inh ibited terfenadine N-dealkylation with K-i values of 10 +/- 4, 10 +/- 3 and 68 +/- 15 mu M respectively. Inhibition of the C-hydroxylation p athway yielded noncompetitive K-i values of 41 +/- 4, 67 +/- 13 and 31 0 +/- 40 mu M respectively. Conclusions Nefazodone and sertraline were moderately weak in vitro inhibitors of terfenadine metabolism while f luoxetine was a very weak inhibitor. Clinically significant interactio n of terfenadine is more likely with nefazodone than sertraline or flu oxetine since therapeutic plasma levels of nefazodone are comparativel y higher.