Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants

Abstract

The aim of this study was to investigate the influence of tricyclic antidepressants (imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2D, measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg(-1) i.p.; desipramine, fluoxetine, sertraline 5 mg kg(-1) i.p.; mirtazapine 3 mg kg(-1) i.p.), in the absence of the antidepressants in-vitro. Antidepressants decreased the activity of the rat CYP2D by competitive inhibition of the enzyme, the potency of their inhibitory effect being as follows: clomipramine (K(i) = 14 microM) > sertraline approximate, equals fluoxetine (K(i) = 17 and 16 microM, respectively) > imipramine approximate, equals amitriptyline (K(i) = 26 and 25 microM, respectively) > desipramine (K(i) = 44 microM) > nefazodone (K(i) = 55 microM) > mirtazapine (K(i) = 107 microM). A one-day treatment with antidepressants caused a significant decrease in the CYP2D activity after imipramine, fluoxetine and sertraline. After prolonged administration of antidepressants, the decreased CYP2D activity produced by imipramine, fluoxetine and sertraline was still maintained. Moreover, amitriptyline and nefazodone significantly decreased, while mirtazapine increased the activity of the enzyme. Desipramine and clomipramine did not produce any effect when administered in-vivo. The obtained results indicate three different mechanisms of the antidepressants-CYP2D interaction: firstly, competitive inhibition of CYP2D shown in-vitro, the inhibitory effects of tricyclic antidepressants and SSRIs being stronger than those of novel drugs; secondly, in-vivo inhibition of CYP2D produced by both one-day and chronic treatment with tricyclic antidepressants (except for desipramine and clomipramine) and SSRIs, which suggests inactivation of the enzyme apoprotein by reactive metabolites; and thirdly, in-vivo inhibition by nefazodone and induction by mirtazapine of CYP2D produced only by chronic treatment with the drugs, which suggests their influence on the enzyme regulation.

Vesicular glutamate transporter mRNA expression in the medial temporal lobe in major depressive disorder, bipolar disorder, and schizophrenia

“…In the second experiment, rats received daily subcutaneous injection of haloperidol (2 mg/kg/day), clozapine (20 mg/kg/day), or acidified DMSO for 28 consecutive days (n = 10 per group). Drug doses were selected based on previously published studies that found significant effects on dependent measures with the doses similar to those employed in the present study [fluoxetine (38–42), valproate (43–48), imipramine (49–52), haloperidol (53–55), clozapine (56–58)]. Twenty‐four hours following the last injection, animals were sacrificed by decapitation; brains were rapidly removed, snap frozen in isopentane, and cryostat sectioned (15 μm) for in situ hybridization.…”

NTP‐CERHR Expert Panel Report on the reproductive and developmental toxicity of fluoxetine

“…Fluoxetine and norfluoxetine are inhibitors of CYP2D6 and fluoxetine is an inhibitor of CYP2C and CYP3A4 (Brosen and Skjelbo, 1991; Alfaro et al, 1999; 2000; Daniel et al, 2002). These enzymes are involved in the metabolism of other drugs as described previously.…”

Mechanism-based inhibition of CYP activities in rat liver by fluoxetine and structurally similar alkylamines

“…Therapy with SSRIs and tricyclic antidepressants is likely to be ongoing and involve combinations with tranquillisers, sedative-hypnotics and other drugs. Pharmacokinetic interactions have been reported during therapy with FLU and other SSRIs (Baumann 1996, Harvey andPreskorn 2001) and in vitro studies have established that the drugs inhibit hepatic CYPs that catalyse oxidative drug metabolism (Kobayashi et al 1995, Mayhew et al 2000, Daniel et al 2002. The precise mechanism of the inhibitory action of FLU on CYP enzymes remains unclear.…”