Terfenadine-antidepressant interactions: an in vitro inhibition study using human liver microsomes.
OBJECTIVE
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 Km for microsomes from four human livers was 11+/-5 and 18+/-3 microM (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 microM respectively. Inhibition of the C-hydroxylation pathway yielded noncompetitive K(i) values of 41+/-4, 67+/-13 and 310+/-40 microM 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.
Jurima-Romet
M
M
Bureau of Drug Research, Therapeutic Products Directorate, Health Canada, Ottawa, Canada.
Wright
M
M
Neigh
S
S
D000478:Alkylation; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005473:Fluoxetine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010879:Piperazines; D020280:Sertraline / Q000494:pharmacology; D016593:Terfenadine / Q000493:pharmacokinetics*; D014230:Triazoles / Q000494:pharmacology
D018687:Antidepressive Agents, Second-Generation; D006634:Histamine H1 Antagonists; D010879:Piperazines; D014230:Triazoles; D005473:Fluoxetine; C051752:nefazodone; D016593:Terfenadine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D020280:Sertraline