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 si gnificance the ability of the novel antidepressant, venlafaxine, to in hibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compare d with the selective serotonin re-uptake inhibitors, fluoxetine, sertr aline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450s was also studied (CYP3A4, CYP2D6, CYP1A2). M ethods Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxyla tion were determined from Dixon plots of control and inhibited rate da ta in human hepatic microsomal incubations. The inhibitory effect of i mipramine and desipramine on liver microsomal CYP2D6 dependent venlafa xine O-demethylation was determined similarly. Venlafaxine's IC50 valu es for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of pr obe substrate activities (testosterone bp-hydroxylation, ethoxyresoruf in O-dealkylase and tolbutamide 4-hydroxylation, respectively). Method s 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 i n human hepatic microsomal incubations. The inhibitory effect of imipr amine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC50 values f or CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone bp-hydroxylation, ethoxyresorufin O -dealkylase and tolbutamide 4-hydroxylation, respectively). Results Fl uoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipra mine 2-hydroxylase activity (K-i values of 1.6 +/- 0.8, 3.2 +/- 0.8 an d 8.0 +/- 4.3 mu M, respectively; mean +/- s.d., n = 3), while sertral ine was less inhibitory (K, of 24.7 +/- 8.9 mu M). Fluoxetine also mar kedly inhibited desipramine 2-hydroxylation with a K-i of 1.3 +/- 0.5 mu M. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxy lation (K-i of 41.0 +/- 9.5 mu M) than the SSRIs that were studied. Im ipramine and desipramine gave marked inhibition of CYP2D6 dependent ve nlafaxine 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 testoste rone 6 beta-hydroxylase (CYP3A4) activities at concentrations of up to 1 mM. Conclusions It is concluded that venlafaxine has a low potentia l to inhibit the metabolism of substrates for CYP2D6 Such as imipramin e and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other majo r human hepatic P450s.