Effect of venlafaxine on the pharmacokinetics of alprazolam

Potential pharmacokinetic effects of venlafaxine on alprazolam, a substrate of the cytochrome pigment 450 (CYP) isoenzyme CYP3A4, were investigated in 16 healthy volunteers. A single 2-mg oral dose of alprazolam was combined with steady-state levels of venlafaxine administered orally at 75 mg twice daily. The levels of alprazolam in plasma and of alprazolam, alpha-hydroxyalprazolam, and 4-hydroxyalprazolam in urine were determined. Steady-state venlafaxine and O-desmethylvenlafaxine concentrations in plasma were reached before venlafaxine was coadministered with alprazolam. Coadministering venlafaxine increased the apparent oral clearance and volume of distribution of alprazolam by 36 percent and 9 percent, respectively, and decreased the alprazolam area under the concentration-time curve and half-life by 29 percent and 21 percent, respectively. There were small but statistically significant increases in mean baseline scores for the digit-symbol substitution and symbol copying tests, probably reflecting a time-dependent learning effect. The maximum score decrease from baseline for these two tests also increased, possibly representing an additive effect of alprazolam and venlafaxine. Overall, venlafaxine did not inhibit the CYP3A4-mediated metabolism of alprazolam in vivo, which corroborates other in vitro and in vivo data showing a lack of CYP3A4 inhibition with venlafaxine.