The strong clinical interaction between bupropion and CYP2D6 is primarily mediated through bupropion metabolites and their stereoisomers: A paradigm for evaluating metabolites in drug-drug interaction risk.

Abstract

Bupropion (BUP) is a potent clinical inhibitor of CYP2D6, although the specific mechanisms underlying this interaction are not fully understood. We comprehensively evaluated the inhibition potencies of racemic BUP and its stereoisomers, as well as its major metabolites (4-hydroxybupropion [OHBUP], threohydrobupropion [THBUP], and erythrohydrobupropion [EHBUP]), on CYP2D6-mediated dextromethorphan O-demethylation in pooled human liver microsomes. The K_i value for racemic EHBUP was 5.5-, 11.4-, and 13-fold lower than those for THBUP, OHBUP, and BUP, respectively. THBUP demonstrated over 2-fold greater potency than OHBUP and BUP. Additionally, RR-THBUP had a 2.1-fold lower K_i value than SS-THBUP, while S-BUP and RR-OHBUP exhibited 3.0-fold and 1.5-fold lower K_i values than R-BUP and SS-OHBUP, respectively, indicating modest stereoselective inhibition. The K_i values of stereoisomers EHBUP were comparable. Using a mechanistic static interaction model that incorporated in vitro K_i value and unbound steady-state concentration in plasma (C_max) or estimated liver concentrations of each inhibitor, we found significant underprediction of the observed clinical BUP-CYP2D6 interaction, indicating that no single inhibitor can predict observed in vivo BUP-CYP2D6 interaction. Accurate predictions of observed clinical interactions were achieved using all racemic (within 11.6%) or all stereoisomeric forms (within 5.4%) of BUP and its metabolites, along with their liver concentrations (but not plasma concentrations). Our findings highlight the crucial role of circulating BUP metabolites, particularly the summation of EHBUP and THBUP or their stereoisomers, in the in vivo inhibition of CYP2D6 by BUP. These data provide mechanistic and quantitative insight into the partially understood clinical CYP2D6-dependent interactions associated with BUP. SIGNIFICANCE STATEMENT: This article describes comprehensively the inhibition of CYP2D6 by racemic and stereoisomers of bupropion (BUP) and its main metabolites in pooled human liver microsomes. The strong interaction between BUP and CYP2D6 observed clinically is mainly due to BUP metabolites and inhibition is stereospecific. Accounting for inhibition constants and steady-state unbound estimated liver (but not plasma) concentrations of all racemic or all stereoisomers accurately predicted the clinically observed BUP-CYP2D6 interactions.