Haloperidol metabolites inhibit CYP2D6 catalyzed dextromethorphan O-demethylation in vitro

Haloperidol is known for its clinically significant interaction with drugs that are metabolized by CYP2D6, but the clinical effect was not sufficiently explained by the in vitro CYP2D6 inhibitory potency of haloperidol itself due to its low therapeutic concentration. To evaluate the involvement of haloperidol metabolites in drug interactions with CYP2D6 substrates, several haloperidol metabolites were assessed for their inhibitory effect on CYP2D6 catalyzed dextromethorphan O-demethylation using human liver microsomes and human cDNA-expressed CYP2D6 in vitro. Reduced haloperidol, N-dealkylated metabolites CPHP and FBPA competitively inhibited the CYP2D6 catalyzed reaction, while the inhibition by pyridinium metabolite HPP was best explained by noncompetitive inhibition model with nonlinear regression analysis. Estimated mean K_i values of these metabolites were comparable with that of haloperidol (Table). Haloperidol Metabolites Type of Inhibition K_i Haloperidol Partial Competitive 7.2 Reduced Haloperidol Partial Competitive 0.5 CPHP Competitive 22.9 FBPA Competitive 338.3 HPP+ Noncompetitive 1.5 These data suggest that most haloperidol metabolites have strong inhibitory effect of CYP2D6 catalyzed reaction like haloperidol and these metabolites may play an important role in the haloperidol drug interaction with CYP2D6 substrates. These data also increase our understanding of haloperidol structure-CYP2D6 inhibition relationship.