Background: Bupropion (BUP) is widely used as an antidepressant and smoking cessation
aid. There are three major pharmacologically active metabolites of BUP, Erythrohydrobupropion (EB),
Hydroxybupropion (OHB) and Threohydrobupropion (TB). At present, the mechanisms underlying the
overall disposition and systemic clearance of BUP and its metabolites have not been well understood,
and the role of transporters has not been studied.
Objective: The goal of this study was to investigate whether BUP and its active metabolites are substrates
of the major hepatic uptake and efflux transporters.
Method: CHO or HEK293 cell lines or plasma membrane vesicles that overexpress OATP1B1,
OATP1B3, OATP2B1, OATP4A1, OCT1, BCRP, MRP2 or P-gp were used in cellular or vesicle uptake
and inhibition assays. Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) was
used to quantify transport activity.
Results: BUP and its major active metabolites were actively transported into the CHO or HEK293 cells
overexpressing OATP1B1, OATP1B3 or OATP2B1; however, such cellular active uptake could not be
inhibited at all by prototypical inhibitors of any of the OATP transporters. These compounds were not
transported by OCT1, BCRP, MRP2 or P-gp either. These results suggest that the major known hepatic
transporters likely play a minor role in the overall disposition and systemic clearance of BUP and its
active metabolites in humans. We also demonstrated that BUP and its metabolites were not transported
by OATP4A1, an uptake transporter on the apical membrane of placental syncytiotrophoblasts, suggesting
that OATP4A1 is not responsible for the transfer of BUP and its metabolites from the maternal
blood to the fetal compartment across the placental barrier in pregnant women.
Conclusion: BUP and metabolites are not substrates of the major hepatic transporters tested and thus
these hepatic transporters likely do not play a role in the overall disposition of the drug. Our results also
suggest that caution should be taken when using the model CHO and HEK293 cell lines to evaluate potential
roles of transporters in drug disposition.