COMMENT: The fact that desipramine levels were doubled with the addition of bupropion was a surprising clinical event because its Ki is so high that it was though not possible for it to significantly inhibit CYP2D6 (IC50 is more than 50uM). In this in vitro study, it is shown that the actual culprits (perpetrators) of CYP2D6 inhibition are 2 of bupropion's active metabolites that are competitive inhibitors of CYP2D6- with a Ki of 1.7 for the latter in contrast to the Ki of 2.8 for desipramine's inhibition of CYP2D6. Although this in vitro finding fits nicely into predictive models of the drug interaction, it must be remember that in vitro data sometimes does not translate into in vivo data.

There are documented clinical drug-drug interactions between bupropion and the CYP2D6-metabolised drug, desipramine, resulting in marked (5-fold) increases in desipramine exposure. This finding was unexpected as CYP2D6 does not play a significant role in clearance, and bupropion and its major active metabolite, hydroxybupropion, are not strong CYP2D6 inhibitors in vitro. The aims of this study were to investigate whether bupropion's reductive metabolites contribute to the drug interaction with desipramine. In human liver microsomes using the CYP2D6 probe substrate bufuralol, bupropion's metabolites were more potent inhibitors of CYP2D6 activity (Ki = 1.7 microM and 5.4 microM, respectively) than hydroxybupropion (Ki = 13microM) or bupropion (Ki = 21microM). Further, neither bupropion nor its metabolites were metabolism-dependent CYP2D6 inhibitors. Using the in vitro kinetic constants and estimated liver concentrations of bupropion and its metabolites, modeling was able to predict within two-fold the increase in desipramine exposure observed when co-administered with bupropion. This work indicates that the reductive metabolites of bupropion are potent competitive CYP2D6 inhibitors in vivo and provides a mechanistic explanation for the clinical drug-drug interaction between bupropion and desipramine.

PMID: 18420781