Effect of antidepressant drugs on cytochrome P450 2C11 (CYP2C11) in rat liver

摘要

Bacground: Rat CYP2C11 (besides CYP2C6) can be regarded as a functional counterpart of human CYP2C9. The aim of the pres-ent study was to investigate the influence of classic and novel antidepressant drugs on the activity of CYP2C11, measured as a rate oftestosterone 2a- and 16a-hydroxylation.Methods: The reaction was studied in control liver microsomes in the presence of antidepressants, as well as in microsomes fromrats treated intraperitoneally (ip) with pharmacological doses of the tested drugs (imipramine, amitriptyline, clomipramine, nefazo-done – 10 mg/kg ip; desipramine, fluoxetine, sertraline - 5 mg/kg ip; mirtazapine - 3 mg/kg ip) for one day or two weeks (twicea day), in the absence of antidepressants in vitro.Results: The investigated antidepressant drugs added to control liver microsomes produced certain inhibitory effects on CYP2C11activity, which were moderate (sertraline, nefazodone and clomipramine: KE= 39, 56 and 66 μM, respectively), modest (fluoxetineand amitriptyline: KE= 98 and 108 μM, respectively) or weak (imipramine and desipramine: KE= 191 and 212 μM, respectively).Mirtazapine had no inhibitory effect on CYP2C11 activity. One-day exposure of rats to the antidepressant drugs did not significantlychange the activity of CYP2C11 in liver microsomes; however, imipramine, desipramine and fluoxetine showed a tendency to di-minish the activity of CYP2C11. Of the antidepressants studied, only desipramine and fluoxetine administered chronically elevatedCYP2C11 activity; those effects were positively correlated with the observed increases in the enzyme protein level.Conclusion: Three different mechanisms of the antidepressants-CYP2C11 interaction are postulated: 1) a direct inhibition ofCYP2C11 shown in vitro by nefazodone, SSRIs and TADs; 2) in vivo inhibition of CYP2C11 produced by one-day treatment withimipramine, desipramine and fluoxetine, which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction ofCYP2C11 produced by chronic treatment with desipramine and fluoxetine, which suggests their influence on enzyme regulation