The aim of the present study was to investigate the influence of antidepressants with different chemical structures and mechanisms of action affecting serotonergic and/or noradrenergic systems - tricyclic antidepressant drugs (TAD), selective serotonin reuptake inhibitors (SSRIs) and novel antidepressants (mirtazapine, nefazodone) - on the activity of rat CYP2B measured as the rate of 16beta-hydroxylation of testosterone. The reaction was studied in control liver microsomes in the presence of

more »

... tidepressants, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10; desipramine, fluoxetine, sertraline 5; mirtazapine 3). The obtained K(i) values indicated that nefazodone and the SSRIs sertraline and fluoxetine were the most potent inhibitors of the studied reaction (K(i) = 10-20 microM). The inhibitory effects of TADs were modest (K(i) = 62-85 microM), while mirtazapine was a very weak inhibitor of CYP2B activity (K(i) = 286 microM). After a one-day exposure of rats to the investigated antidepressants, a significant increase in CYP2B activity was only observed after sertraline exposure (300% of the control). Chronic treatment with the antidepressants led to a significant enhancement of CYP2B activity after sertraline, fluoxetine and desipramine (580, 200 and 150% of the control, respectively) treatment, which positively correlated with the observed elevation in CYP2B protein levels. In summary, two different mechanisms of the antidepressant-CYP2B interaction are postulated: 1) a direct inhibition of CYP2B shown in vitro by nefazodone, SSRIs and TADs; 2) in vivo induction of CYP2B produced by prolonged administration of SSRIs and desipramine, which suggests their influence on enzyme regulation. The marked CYP2B-induction produced by SSRIs corresponds with their selective serotonin reuptake inhibition, while the effect of desipramine corresponds with its selective inhibition of noradrenaline reuptake.