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Terfenadine–antidepressant interactions: an in vitro inhibition study using human liver microsomes
Author(s) -
JurimaRomet Malle,
Wright Marcy,
Neigh Scott
Publication year - 1998
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1998.00681.x
Subject(s) - terfenadine , sertraline , nefazodone , pharmacology , chemistry , microsome , cyp3a4 , fluoxetine , antidepressant , endocrinology , metabolism , cytochrome p450 , in vitro , medicine , biochemistry , serotonin , receptor , hippocampus
Aims Inhibition of the metabolism of terfenadine has been associated with 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 the antidepressants at various concentrations. Formation of the two major metabolites of terfenadine was determined by h.p.l.c.Results The apparent K m for microsomes from four human livers was 11±5 and 18±3 μm (mean±s.e.mean) for the N ‐dealkylation and C ‐hydroxylation pathways, respectively. Nefazodone, sertraline and fluoxetine inhibited terfenadine N ‐dealkylation with K i values of 10±4, 10±3 and 68±15 μm respectively. Inhibition of the C ‐hydroxylation pathway yielded noncompetitive K i values of 41±4, 67±13 and 310±40 μm respectively.Conclusions Nefazodone and sertraline were moderately weak in vitro inhibitors of terfenadine metabolism while fluoxetine was a very weak inhibitor. Clinically significant interaction of terfenadine is more likely with nefazodone than sertraline or fluoxetine since therapeutic plasma levels of nefazodone are comparatively higher.