Direct and indirect interactions between, antidepressant drugs and CYP2C6 in the rat liver during long-term treatment

The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clornipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertratine) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as welt as in microsomes of rats treated intraperitoneally (i.p.) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone at 10 mg/kg i.p.; desipramine, fluoxetine, sertratine at 5 mg/kg i.p.; mirtazapine at 3mg/kg i.p.), in the absence of the antidepressants in vitro. Some of the investigated antidepressant drugs added to liver microsomes of control rats inhibited the rate of 7-hydroxylation of warfarin. The obtained Ki values indicated that nefazodone and fluoxetine were the most potent inhibitors of the studied reaction (K-i = 13 and 23 mu M, respectively), while tricyclic antidepressants and sertratine were weak in this respect (K-i=70-127 mu M). A one-day (i.e. 24h) exposure to fluoxetine and mirtazapine resulted in a significant increase in the rate of the 7-hydroxytation of warfarin in rat liver microsomes. The other studied antidepressants did not significantly affect the rate of the CYP2C6-specific reaction. After two-week treatment with the investigated antidepressants, the increase in CYP2C6 activity observed after 24-h exposure to fluoxetine and mirtazapine was more pronounced. Moreover, unlike after one-day exposure, imipramine and sertraline significantly increased the activity of the enzyme. The other tricyclic antidepressants or nefazodone did not produce any significant effect when administered in vivo. The above-described enhancement of CYP2C6 activity correlated positively with the simultaneousLy observed increases in the enzyme protein level, which indicates the enzyme induction. The studied antidepressants increased the CYP2C6 protein level in the liver microsomes of rats after chronic treatment: imipramine to 174.6 +/- 18.3%, fluoxetine to 159.1 +/- 13.7%, sertraline to 135.3 +/- 11.2% and mirtazapine to 138.4 +/- 10.2% of the control. In summary, two different mechanisms of the antidepressant-CYP2C6 interaction have been found to operate in the rat liver: 1) direct inhibition of CYP2C6 shown in vitro mainly for nefazodone and fluoxetine, with their inhibitory effects being somewhat more potent than their action on human CYP2C9; 2) the in vivo induction of CYP2C6 by imipramine, ftuoxetine, sertraline and mirtazapine. (c) 2006 Elsevier B.V. and ECNP. All rights reserved.