Characterizing bupropion metabolism, pharmacokinetics and drug-drug interaction liability

Thesis (Ph.D.)--University of Washington, 2016-06

Bupropion is a norepinephrine and dopamine reuptake inhibitor that is currently indicated for use as an antidepressant (Wellbutrin), a smoking cessation aid (Zyban) and a weight loss therapy in combination with naltrexone (Contrave). Bupropion is also the preferred sensitive in vivo CYP2B6 substrate recommended by the FDA (U.S. Food and Drug Administration Center for Drug Evaluation and Research (CDER), 2012). Efavirenz, the only other CYP2B6 sensitive substrate, is a time dependent inhibitor (Bumpus et al., 2006) and inducer (Kharasch et al., 2012) of CYP2B6, both of which limit its usefulness. Yet, despite its numerous clinical and research applications, there are many gaps in our knowledge of bupropion pharmacokinetics. First of all, bupropion elimination pathways have yet to be fully characterized. Secondly, bupropion causes strong in vivo CYP2D6 inhibition, yet the source of the interaction has not been identified. The goal of this project was to characterize the metabolism of bupropion and elucidate the quantitative aspects of CYP2D6 interaction. Finally, using our knowledge of bupropion metabolism, changes in CYP2B6 and CYP2C19 activity during pregnancy were assessed by evaluating the changes in bupropion PK during pregnancy. Because less than 30% of the bupropion dose is reportedly recovered as bupropion, OH-bupropion, threohydrobupropion and erythrohydrobupropion and their conjugates (Welch et al., 1987), additional metabolites were isolated from human urine and characterized via MS/MS, NMR and UV to allow for full characterization of bupropion elimination. Three novel metabolites 4-OH-bupropion, erythro-4-OH-hydrobupropion, and threo-4’-OH-hydrobupropion were isolated and identified. The relative contribution of each elimination pathway was assessed through in vitro incubations in human liver S9 fractions or recombinant P450. CYP2B6 and CYP2C19 were found to be quantitatively minor elimination pathways, contributing to only 23 and 5% of total bupropion clearance. The majority of bupropion is cleared via reduction to threohydrobupropion (66%) and erythrohydrobupropion (6%). To elucidate the cause of the bupropion-CYP2D6 interaction, the inhibition potential the individual stereoisomers of bupropion and OH-bupropion was investigated but these stereoisomers were not predicted to account for the observed magnitude of the in vivo interaction. However, bupropion and all of its metabolites were found to significantly downregulate CYP2D6 on the basis of activity and mRNA levels. Inclusion of downregulation into static predictions resulted in accurate predictions of the observed drug interaction. To evaulate the effects of pregnancy on bupropion pharmacokinetics, plasma concentrations and urine amounts of bupropion and its metabolites were measured both during pregnancy and post partum in 5 subjects. While plasma levels of bupropion and its metabolites remained steady, a significant two-fold change in OH-bupropion formation clearance was observed in the third trimester, when compared to postpartum. This result suggested that CYP2B6 is substantially induced in pregnancy and thus caution should be exercised when prescribing CYP2B6 substrates to pregnant women.