Abstract
Bupropion is a widely used antidepressant, smoking cessation aid, and weight-loss therapy. It is administered as a racemic mixture, but the pharmacokinetics and activity of bupropion are stereoselective. The activity and side effects of bupropion are attributed to bupropion and its metabolites S,S- and R,R-OH-bupropion, threohydrobupropion, and erythrohydrobupropion. Yet the stereoselective metabolism in vitro and the enzymes contributing to the stereoselective disposition of bupropion have not been characterized. In humans, the fraction of bupropion metabolized (fm) to the CYP2B6 probe metabolite OH-bupropion is 5–16%, but ticlopidine increases bupropion exposure by 61%, suggesting a 40% CYP2B6 and/or CYP2C19 fm for bupropion. Yet, the CYP2C19 contribution to bupropion clearance has not been defined, and the enzymes contributing to overall bupropion metabolite formation have not been fully characterized. The aim of this study was to characterize the stereoselective metabolism of bupropion in vitro to explain the stereoselective pharmacokinetics and the effect of drug-drug interactions (DDIs) and CYP2C19 pharmacogenetics on bupropion exposure. The data predict that threohydrobupropion accounts for 50 and 82%, OH-bupropion for 34 and 12%, erythrohydrobupropion for 8 and 4%, and 4′-OH-bupropion for 8 and 2% of overall R- and S-bupropion clearance, respectively. The fm,CYP2B6 was predicted to be 21%, and the fm,CYP2C19, 6% for racemic bupropion. Importantly, ticlopidine was found to inhibit all metabolic pathways of bupropion in vitro, including threohydrobupropion, erythrohydrobupropion, and 4′OH-bupropion formation, explaining the in vivo DDI. The stereoselective pharmacokinetics of bupropion were quantitatively explained by the in vitro metabolic clearances and in vivo interconversion between bupropion stereoisomers.
Highlights
Bupropion is an antidepressant used as a smoking cessation aid and weight loss therapy
The aim of this study was to characterize the stereoselective metabolism of bupropion in vitro to explain the stereoselective pharmacokinetics and the effect of drug-drug interactions (DDIs) and CYP2C19 pharmacogenetics on bupropion exposure
To determine the enzymes contributing to R,R- and S,SOH-bupropion formation, R- and S-bupropion were incubated with a panel of recombinant human cytochrome P450 (P450) enzymes at 100 and 1 mM NADPH before bupropion (1 mM) concentrations
Summary
Bupropion is an antidepressant used as a smoking cessation aid and weight loss therapy. Bupropion is cleared via oxidation by cytochrome P450s (P450s) to OH-bupropion and 49-OH-bupropion (Faucette et al, 2000; Benowitz et al, 2013; Sager et al, 2016) and reduction by 11b-hydroxysteroid dehydrogenase-1 (11b-HSD-1) and aldoketoreductase(s) to threohydrobupropion and erythrohydrobupropion (Meyer et al, 2013; Skarydova et al, 2014; Connarn et al, 2015) (Fig. 1). OH-bupropion, threohydrobupropion, and erythrohydrobupropion have plasma concentrations that exceed bupropion concentrations by 3- to 30-fold (Benowitz et al, 2013; Masters et al, 2016), and these metabolites are believed to contribute to bupropion’s pharmacological activity and toxicity (Bondarev et al, 2003; Damaj et al, 2004). Smoking cessation success has a strong dose-response relationship (Hurt et al, 1997), but OH-bupropion concentrations, rather than
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