Effect of venlafaxine on the pharmacokinetics of terfenadine.

The effect of steady-state venlafaxine administration on the single-dose pharmacokinetic profile of terfenadine, a cytochrome pigment (P450) isoenzyme CYP3A4 substrate, and its active acid metabolite (fexofenadine) was evaluated in an open-label, nonrandomized study. Twenty-six healthy subjects were given a 120-mg oral dose of terfenadine before and after venlafaxine was titrated up to steady-state. Blood samples were drawn before terfenadine dosing and at various intervals for 48 hours after dosing to measure plasma concentrations of terfenadine and its acid metabolite. Blood samples were obtained before each venlafaxine dose to measure trough levels of venlafaxine and O-desmethyl-venlafaxine. Single-dose pharmacokinetic parameters of terfenadine did not change significantly in the presence of steady-state venlafaxine. However, terfenadine acid metabolite area under the plasma concentration-time curve decreased by approximately 25 percent; this was not thought to be related to the P450 isoenzyme system. These results are consistent with in vitro studies and in vivo studies with other CYP3A4 substrates, indicating that venlafaxine has a low potential for drug-drug interactions that result from inhibition of the CYP3A4 isoenzyme.