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SHORT COMMUNICATION

An in Vitro Mechanistic Study to Elucidate the Desipramine/Bupropion Clinical Drug-Drug Interaction

Departments of Drug Metabolism and Pharmacokinetics (M.J.R., R.M.W., G.T.G., L.S.-W.) and Clinical Pharmacology and Discovery Medicine (K.T.M.), GlaxoSmithKline, Research Triangle Park, North Carolina; and Department of Drug Metabolism and Pharmacokinetics, Theravance, Inc., South San Francisco, California (D.J.M.)

There are documented clinical drug-drug interactions between bupropion and the CYP2D6-metabolized drug desipramine resulting in marked (5-fold) increases in desipramine exposure. This finding was unexpected as CYP2D6 does not play a significant role in bupropion 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, threohydrobupropion and erythrohydrobupropion, contribute to the drug interaction with desipramine. In human liver microsomes using the CYP2D6 probe substrate bufuralol, erythrohydrobupropion and threohydrobupropion were more potent inhibitors of CYP2D6 activity (K_i = 1.7 and 5.4 µM, respectively) than hydroxybupropion (K_i = 13 µM) or bupropion (K_i = 21 µM). Furthermore, 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 2-fold the increase in desipramine exposure observed when coadministered 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.