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

Bacground: rat cyp2c11 (besides cyp2c6) can be regarded as a functional counterpart of human cyp2c9. the aim of the present study was to investigate the influence of classic and novel antidepressant drugs on the activity of cyp2c11,measured as a rate of testosterone 2a- and 16a-hydroxylation. methods: the reaction was studied in control liver microsomes in the presence of antidepressants,as well as in microsomes from rats treated intraperitoneally (ip) with pharmacological doses of the tested drugs (imipramine,amitriptyline,clomipramine,nefazodone - 10 mg/kg ip; desipramine,fluoxetine,sertraline - 5 mg/kg ip; mirtazapine - 3 mg/kg ip) for one day or two weeks (twice a day),in the absence of antidepressants in vitro. results: the investigated antidepressant drugs added to control liver microsomes produced certain inhibitory effects on cyp2c11 activity,which were moderate (sertraline,nefazodone and clomipramine: ki = 39,56 and 66 μm,respectively),modest (fluoxetine and amitriptyline: ki = 98 and 108 μm,respectively) or weak (imipramine and desipramine: ki = 191 and 212 μm,respectively). mirtazapine had no inhibitory effect on cyp2c11 activity. one-day exposure of rats to the antidepressant drugs did not significantly change the activity of cyp2c11 in liver microsomes; however,imipramine,desipramine and fluoxetine showed a tendency to diminish the activity of cyp2c11. of the antidepressants studied,only desipramine and fluoxetine administered chronically elevated cyp2c11 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 of cyp2c11 shown in vitro by nefazodone,ssris and tads; 2) in vivo inhibition of cyp2c11 produced by one-day treatment with imipramine,desipramine and fluoxetine,which suggests inactivation of the enzyme by reactive metabolites; 3) in vivo induction of cyp2c11 produced by chronic treatment with desipramine and fluoxetine,which suggests their influence on enzyme regulation.copyright © 2013 by institute of pharmacology polish academy of sciences.