Terfenadine-antidepressant interactions: an in vitro inhibition study using human liver microsomes.

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 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.

Induction of cytochrome P450 3A by retinoids in rat hepatocyte culture.

1. Rat hepatocytes cultured on a Matrigel matrix were exposed for 48 h to all-trans-retinoic acid, 9-cis-retinoic acid, 13-cis-retinoic acid or fenretinide. 2. Cytochrome P450 3A (CYP3A) RNA levels were increased by approximately eightfold in hepatocytes treated with the retinoids compared to control cultures. 3. CYP1A1 and CYP1A2 RNA levels were only slightly affected or unaffected by the retinoids. 4. The induction of CYP3A by these therapeutically-useful retinoids suggests that they may share a common mechanism for accelerated drug catabolism and acquired clinical resistance.