Serum Concentration-Dependent Inhibition of CYP2D6 by Bupropion and Doxepin: Implications for Venlafaxine and Risperidone Metabolism

Abstract The increasing use of antidepressant combinations necessitates a deeper understanding of drug–drug interactions. This study investigated serum concentration-dependent CYP2D6 inhibition by bupropion (via hydroxybupropion) and doxepin at antidepressant doses, using venlafaxine and risperidone as victim drugs. Therapeutic drug monitoring data from inpatients at the University Hospital of Würzburg (2018–2023) were retrospectively analyzed across four interaction groups (hydroxybupropion–venlafaxine, doxepin–venlafaxine, doxepin–risperidone, and hydroxybupropion–risperidone) with controls lacking CYP2D6 inhibitors. Associations between inhibitor concentrations and victim drug levels were assessed linearly. Nonlinear regression (four-parameter logistic model) was applied to relate inhibitor concentrations to metabolite-to-parent ratios; when the model fit was adequate, the half-maximal inhibitory concentration/90% inhibitory concentration values were estimated. Receiver operating characteristic analysis identified inhibitor concentration thresholds for phenoconversion to poor metabolizer status. Hydroxybupropion and doxepin concentrations were positively associated with venlafaxine, risperidone, and venlafaxine active moiety levels (p ≤ 0.02). Adequate sigmoidal curve fitting demonstrated a concentration-dependent inverse association between inhibitor levels and metabolite-to-parent ratios for venlafaxine with hydroxybupropion and doxepin, and risperidone with hydroxybupropion, but not risperidone with doxepin. The half-maximal inhibitory concentration values were 120.4 ng/mL and 28.16 ng/mL for hydroxybupropion (venlafaxine and risperidone, respectively) and 24.4 ng/mL for doxepin (venlafaxine). Phenoconversion thresholds were identified for hydroxybupropion (venlafaxine: 328.5 ng/mL and risperidone: 110.5 ng/mL) and doxepin (venlafaxine: 35 ng/mL and risperidone: 70.5 ng/mL). Hydroxybupropion and doxepin exert serum concentration-dependent inhibition of CYP2D6 activity, significantly affecting the metabolism of venlafaxine and risperidone. These effects and a phenoconversion into poor metabolizer status were detectable at subtherapeutic hydroxybupropion and therapeutic antidepressant doxepin levels. Monitoring inhibitor and victim-drug concentrations may aid in managing clinically relevant CYP2D6-mediated interactions.