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

Cytochrome P450 (CYP3A4, CYP2A6, CYP2C19, CYP2D6)의 약물대사에 대한 bupropion의 영향

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 ($Ki\;=\;1.631{\pm}0.544\;{\mu}M$). and bufuralol 1'-hydroxylase ($Ki\;=\;1.017{\pm}0.284\;{\mu}M$). The IC50 values for inhibition of CYP2C19 (coumarin, $1\;{\mu}M)$ and CYP2D6 (bufuralol, $1\;{\mu}M$) index reaction by bupropion were $3.36\;{\mu}M$ and $6.45\;{\mu}M$, 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.