Effect of venlafaxine versus fluoxetine on metabolism of dextromethorphan,a CYP2D6 probe

Two antidepressants, venlafaxine and fluoxetine, were evaluated in vivo for their effect on cytochrome P450 2D6 (CYP2D6) activity, measured by the rat io of dextromethorphan, a sensitive CYP2D6 marker, to its metabolite dextro rphan (i.e., DM:DT) excreted in urine after DM coadministration. Twenty-eig ht healthy extensive metabolizers of CYP2D6 received either venlafaxine (37 .5 mg bid for 7 days, then 75 mg bid until Day 28) or fluoxetine (20 mg dai ly for 28 days); 26 completed the study. Plasma concentrations of both drug s and their active metabolites were determined. DM:DTs were evaluated at ba seline (Day 0), on Days 7 and 28 of dosing, and 2 weeks after drug disconti nuation (Day 42). Steady-state drug and metabolite levels were achieved in both groups by Day 28. Mean DM:DTs for venlafaxine and fluoxetine differed statistically significantly (p < 0.001) on Days 7 28, and 42. Comparisons o f DM:DT as a percentage of baseline values showed that DM:DT increased 1.2- fold for venlafaxine and 9.1-fold for fluoxetine on Day 7 (p < 0.001) and i ncreased 2.1-fold for venlafaxine and 17.1-fold for fluoxetine on Day 28 (p < 0.001). Inhibition of CYP2D6 metabolism persisted for 2 weeks after disc ontinuation of fluoxetine, unlike the case with venlafaxine. These in vivo results confirm in vitro data demonstrating significantly weaker inhibition of CYP2D6 with venlafaxine than with fluoxetine. This suggests that clinic ally significant interactions involving CYP2D6 inhibition could occur betwe en fluoxetine and drugs metabolized by CYP2D6 bur may be less likely to occ ur with venlafaxine. <(c)> 2001 the American College of Clinical Pharmacolo gy.