Effect of selected antidepressant drugs on cytochrome P450 2B (CYP2B) in rat liver. An in vitro and in vivo study.
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 antidepressants, 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.
Haduch
Anna
A
Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, PL 31-343 Kraków, Poland.
Wójcikowski
Jacek
J
Daniel
Władysława A
WA
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar
D000928:Antidepressive Agents; D019362:Cytochrome P-450 CYP2B1