EVALUATION OF THE CONTRIBUTION OF CYTOCHROME P450 3A4 TO HUMAN LIVER MICROSOMAL BUPROPION HYDROXYLATION

This paper is available online at http://dmd.aspetjournals.org ABSTRACT: The purpose of this investigation was to evaluate the role of cytochrome P450 (CYP) 3A4 in human liver microsomal bupropion (BUP) hydroxylation. Across the BUP concentration range of 0.075 to 12 mM, cDNA-expressed CYP3A4 demonstrated BUP hydroxylase activity only when incubated with concentrations >4 mM. When assayed at 12 mM BUP, cDNA-expressed CYP3A4 catalyzed BUP hydroxylation at a 30-fold lower rate than cDNA-expressed CYP2B6 (0.2 versus 7 pmol/min/pmol of P450 Bupropion (BUP) 1 is a second-generation antidepressant agent that is also used in the management of smoking cessation. This drug undergoes extensive hepatic metabolism in humans via oxidative and reductive pathways Clinical pharmacokinetic studies have demonstrated 3-to 10-fold interindividual differences in HBUP C max and AUC In a prior in vitro study reported in abstract form, CYP3A4 demonstrated the second highest rate of BUP hydroxylation among a panel of cDNA-expressed P450 isozyme