Venlafaxine: In vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; Comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYPIA2

Aims In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450s was also studied (CYP3A4, CYP2D6, CYP1A2). Methods Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone bp-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). Methods K-i values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone bp-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). Results Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (K-i values of 1.6 +/- 0.8, 3.2 +/- 0.8 and 8.0 +/- 4.3 mu M, respectively; mean +/- s.d., n = 3), while sertraline was less inhibitory (K, of 24.7 +/- 8.9 mu M). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a K-i of 1.3 +/- 0.5 mu M. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (K-i of 41.0 +/- 9.5 mu M) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (K-i values of 3.9 +/- 1.7 and 1.7 +/- 0.9 mu M, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. Conclusions It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 Such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.