title: Effect of antidepressant drugs on cytochrome P450 2C11 (CYP2C11) in rat liver.
abstract: BACKGROUND
  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 2α and 16α-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343 Kraków, Poland. wojcikow@if-pan.krakow.pl.
authors.forename: Jacek
authors.initials: J
authors.lastname: Wójcikowski
authors.forename: Anna
authors.initials: A
authors.lastname: Haduch
authors.forename: Władysława Anna
authors.initials: WA
authors.lastname: Daniel
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001711:Biotransformation; D000072467:Cytochrome P450 Family 2; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006900:Hydroxylation; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D013739:Testosterone; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase