# Mechanisms Underlying Stereoselective Bupropion Metabolism and Complex Drug Interactions.

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $336,869

## Abstract

Bupropion (BUP) is widely used for the treatment of major depression and seasonal affective disorder and as a
smoking cessation aid. Marked variability in clinical response among patients and clinically important CYP2D6-
dependent drug-drug interactions (DDIs) often compromise effective and safe BUP use. Our long-term goal is
to improve BUP therapy through identification of mechanisms influencing BUP's efficacy, toxicity and DDIs. As
a first step, we will comprehensively elucidate the sequential stereoselective metabolism and disposition of
BUP and identify mechanisms underlying CYP2D6-dependent DDIs. BUP biotransformation to 4-hydroxyBUP
and threo-/erythro-hydroBUP by CYP2B6 and carbonyl reductases, respectively, is a major determinant of
BUP's clinical efficacy, toxicity and DDIs. These metabolites exhibit considerable accumulation in plasma
compared to BUP with widely varying plasma exposures among patients and this variability predicts treatment
outcomes and side effects. To date, specific mechanisms responsible for this inter-patient variability remain
unknown. BUP is administered as a racemic mixture. Its biotransformation to the active metabolites introduces
additional chiral centers, generating multiple diastereomers with unique pharmacological profiles. Insights into
the complex metabolism of BUP would be a major advance to the understanding of variable active metabolites
disposition, effect and DDIs. A critical barrier to evaluating stereoselective metabolism of BUP has been the
lack of reliable analytical methods that allow baseline resolution and quantification of different stereoisomers of
the primary and secondary metabolites of BUP. As detailed in the Preliminary Studies section, we overcame
this critical barrier by developing and validating the first novel chiral and achiral LC-MS/MS methods and
demonstrated marked stereoselective metabolism and disposition in vitro and in vivo. In this proposal,
mechanisms underlying the stereoselective sequential metabolism and disposition of BUP and associated
CYP2D6-dependent DDIs will be identified. In Aim 1, critical pathways and enzymes involved in the
stereoselective BUP clearance leading to formation and subsequent elimination of its active metabolites will be
identified using human hepatic and extrahepatic sub-cellular fractions. In Aim 2, the inhibitory potency of
stereoisomers of BUP and metabolites towards CYP2D6 activity will be tested in human liver microsomes and
expressed CYP2D6. A comprehensive stepwise PBPK modeling approach will be utilized in Aim 3 to
quantitatively describe steady state BUP and metabolite disposition and predict in vivo BUP DDIs. In Aim 4,
the steady-state stereoselective disposition of BUP and metabolites and the time course (onset), extent
(maximum inhibition) and offset of CYP2D6 inhibition will be tested in healthy volunteers. Insights gained from
these integrated in vitro, in silico and in vivo studies on the complex stereospecific sequential metabolism ...

## Key facts

- **NIH application ID:** 9960529
- **Project number:** 5R01GM121707-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Zeruesenay Desta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $336,869
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960529

## Citation

> US National Institutes of Health, RePORTER application 9960529, Mechanisms Underlying Stereoselective Bupropion Metabolism and Complex Drug Interactions. (5R01GM121707-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9960529. Licensed CC0.

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