TY - JOUR T1 - CYP2B6 Mediates the In Vitro Hydroxylation of Bupropion: Potential Drug Interactions with Other Antidepressants JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1176 LP - 1183 VL - 28 IS - 10 AU - Leah M. Hesse AU - Karthik Venkatakrishnan AU - Michael H. Court AU - Lisa L. von Moltke AU - Su X. Duan AU - Richard I. Shader AU - David J. Greenblatt Y1 - 2000/10/01 UR - http://dmd.aspetjournals.org/content/28/10/1176.abstract N2 - The in vitro biotransformation of bupropion to hydroxybupropion was studied in human liver microsomes and microsomes containing heterologously expressed human cytochromes P450 (CYP). The mean (±S.E.) Km in four human liver microsomes was 89 (±14) μM. In microsomes containing cDNA-expressed CYPs, hydroxybupropion formation was mediated only by CYP2B6 at 50 μM bupropion (Km 85 μM). A CYP2B6 inhibitory antibody produced more than 95% inhibition of bupropion hydroxylation in four human livers. Bupropion hydroxylation activity at 250 μM was highly correlated with S-mephenytoinN-demethylation activity (yielding nirvanol), another CYP2B6-mediated reaction, in a panel of 32 human livers (r = 0.94). The CYP2B6 content of 12 human livers highly correlated with bupropion hydroxylation activity (r = 0.96). Thus bupropion hydroxylation is mediated almost exclusively by CYP2B6 and can serve as an index reaction reflecting activity of this isoform. IC50values for inhibition of a CYP2D6 index reaction (dextromethorphanO-demethylation) by bupropion and hydroxybupropion were 58 and 74 μM, respectively. This suggests a low inhibitory potency versus CYP2D6, the clinical importance of which is not established. Since bupropion is frequently coadministered with other antidepressants, IC50 values (μM) for inhibition of bupropion hydroxylation were determined as follows: paroxetine (1.6), fluvoxamine (6.1), sertraline (3.2), desmethylsertraline (19.9), fluoxetine (59.5), norfluoxetine (4.2), and nefazodone (25.4). Bupropion hydroxylation was only weakly inhibited by venlafaxine,O-desmethylvenlafaxine, citalopram, and desmethylcitalopram. The inhibition of bupropion hydroxylation in vitro by a number of newer antidepressants suggests the potential for clinical drug interactions. The American Society for Pharmacology and Experimental Therapeutics ER -