Chirality and neuropsychiatric drugs: an update on stereoselective disposition and clinical pharmacokinetics of bupropion

1. Bupropion, an antidepressant drug has been approved as a racemate containing equal amounts of R- and S-enantiomers. Recently, the chirality of bupropion has received significant attention in the delineation of stereoselective pharmacokinetic (PK) and disposition data. Although the non-stereoselective metabolism of bupropion was well established, the emerging data suggest that bupropion exhibits complex stereoselective metabolism, leading to the formation of various stereoisomeric metabolites. Along with the chiral PKs of bupropion, hydroxybupropion, threohydrobupropion and erythrohydrobupropion, the metabolism data also provided insights into the roles of both CYP2B6 and CYP2C19 enzymes in the stereoselective disposition. Furthermore, the metabolism studies also suggested specific involvement of CYP2B6 pathway in the stereoselective hydroxylation of bupropion to R,R-hydroxybupropion, which was considered as a better marker for CYP2B6 activity. 2. Other significant learnings were: (1) understanding the in vivo CYP2D6 inhibitory potential of bupropion with respect to the chirality of parent drug and the metabolites; (2) the potential involvement of bupropion and metabolites towards significant down regulation of CYP2D6 mRNA; (3) significant in vivo CYP2D6 inhibitory activity (86%) exhibited by R,R-hydroxybupropion and threohydrobupropion. 3. The newly published data on chiral PKs and disposition of bupropion and its metabolites can be used to gauge the drug–drug interaction potential when bupropion is combined in clinical therapy. Moreover, such data would be useful to understand the consequences (if any), due to the combination of bupropion with other drugs both from a safety and efficacy perspective because of the prevalence of polypharmacy situations in many therapeutic areas including CNS indications.