Effects of bupropion on oxidation metabolism catalyzed by human cytochrome P450 isoenzymes (CYP3A4, CYP2A6, CYP2C19 and CYP2D6)

Abstract

Background: Bupropion is an antidepressant and a non-nicotine aid used in smoking cessation. It blocks the neuronal uptake of serotonin and norepinephrine and inhibits the neuronal reuptake of dopamine. Although several in vitro study demonstrated that CYP2D6 activity was inhibited by bupropion, there is no in vitro study that directly reports the inhibitory effects of bupropion on human major CYP isoforms. In the present study, we investigated the inhibitory effects and mechanism-based inactivation potencies of bupropion for human CYP2C19, CYP2D6, CYP2A6 and CYP3A4 activities. Methods: In vitro study was performed using microsomes from baculovirus-infected insect cells expressing specific human CYP isoforms. The specific activities for human CYP isoforms included in this study were S-mephenytoin 4'-hydroxylation (CYP2C19), bufuralol 1'-hydroxylation (CYP2D6), testosterone 6-hydroxylation (CYP3A4), and coumarin 7-hydroxylation (CYP2A6). Results: Bupropion competitively inhibited S-mephenytoin 4'-hydroxylase (Ki = 1.631±0.544 μM) and bufuralol 1'-hydroxylase (Ki = 1.017±0.284 μM). The IC50 values for inhibition of CYP2C19 (coumarin, 1 μM) and CYP2D6 (bufuralol, 1 μM) index reaction by bupropion were 3.36 μM and 6.45 μM, respectively. CYP3A4 and CYP2A6 activities were not significantly inhibited by bupropion. Furthermore, bupropion did not reveal a mechanism-based inactivation of CYP2C19 and CYP2D6. It was clearly shown that CYP2C19 and CYP2D6 were not inactivated by bupropion in a time and concentration dependent manner. Conclusions: Bupropion showed inhibitory effects on CYP2C19 and CYP2D6 activities. These results suggest that bupropion would affect the pharmacokinetics of clinically used drugs that are metabolized by CYP2C19 and CYP2D6.

Assessment of the Effects of Steady-State Bupropion on the Pharmacokinetic Profile of Zolpidem in Healthy Volunteers

“…As for the other isoenzymes involved in zolpidem's metabolism, one in vitro study performed on microsomes from baculovirus-infected insect cells concluded that bupropion demonstrated inhibitory effects on CYP2C19 and CYP2D6 activities while another study performed on rats showed that the antidepressant had no significant effect on CYP2C9mediated tolbutamide hydroxylation. Nonetheless, no enzyme-inducing properties were found for bupropion with regard to the activity of the aforementioned CYP450 isoenzymes [17,26]. The results obtained in the present research are very surprising since this is the first clinical trial to imply that bupropion can possibly alter the activity of CYP3A4.…”