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Characterization of the Stereoselective Disposition of Bupropion and Its Metabolites in Rat Plasma and Brain

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Abstract

Background and Objectives

Bupropion is an atypical antidepressant and smoking cessation aid; its use is associated with wide intersubject variability in efficacy and safety. Knowledge of the brain pharmacokinetics of bupropion and its pharmacologically active metabolites is considered important for understanding the cause–effect relationships driving this variability.

Methods

Brain concentrations from rats administered a 10 mg/kg subcutaneous dose of racemic bupropion were analyzed using a stereoselective LC/MS-MS method. A 2 mg/kg dose of (S,S)-hydroxybupropion, which has comparable pharmacologic potency to bupropion, was administered to a separate group of rats. Plasma exposure and unbound concentrations in both matrices from companion equilibrium dialysis experiments were determined to assess potential carrier-mediated transport at the blood–brain barrier.

Results

Exposures to unbound forms of bupropion enantiomers were similar in plasma; this was also true in brain. This trend held for reductive diastereomer metabolite pairs in the two matrices. Unbound (R,R)-hydroxybupropion exposure was 1.5-fold higher than (S,S)-hydroxybupropion exposure in plasma and brain following bupropion administration. Unbound concentration ratios (Kp,uu) of a given molecular form decreased over time: between 4 and 6 h, these were < 1 for the two bupropion enantiomers, and they were ~ 1 for metabolites that formed. Administration of preformed (S,S)-hydroxybupropion also demonstrated a declining Kp,uu.

Conclusions

The temporal shift in Kp,uu among the different molecular forms provides evidence regarding the operation of carrier-mediated transport and/or within-brain metabolism of bupropion, and, thereby, fresh insight regarding the causes of intersubject variability in the safety and efficacy of bupropion therapy.

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Author notes

  1. Chandrali S. Bhattacharya

    Present address: AstraZeneca, One MedImmune Way, Gaithersburg, MD, 20878, USA

  2. Robert E. Stratford Jr.

    Present address: Otsuka Pharmaceutical Development and Commercialization, Princeton, NJ, 08540, USA

Authors and Affiliations

  1. Department of Pharmacy Practice, Purdue University, Indianapolis, IN, 46202, USA

    Chandrali S. Bhattacharya

  2. Melvin and Bren Simon Comprehensive Cancer Center, Clinical Pharmacology Analytical Core, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Andrea R. Masters & Christine Bach

  3. Melvin and Bren Simon Comprehensive Cancer Center, In Vivo Therapeutics Core, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Anthony L. Sinn & Melissa A. Trowbridge

  4. Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine Research II, 950 West Walnut Street, Indianapolis, IN, 46202, USA

    Robert E. Stratford Jr.

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  1. Chandrali S. Bhattacharya
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Correspondence to Robert E. Stratford Jr..

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Funding

This work was supported in part by a grant from the Indiana Clinical and Translational Sciences Institute by Number UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences. Additional funding was from the Indiana Clinical and Translational Sciences Institute Award Number TL1TR002531 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences. Mass spectrometry work was provided by the Clinical Pharmacology Analytical Core; animal work was provided by the In Vivo Therapeutics Core. Both are core facilities at Indiana University School of Medicine and are supported by the IU Simon Comprehensive Cancer Center Support Grant P30 CA082709.

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Conflict of Interest

All authors report no conflict of interest.

Author Contributions

Participated in research design: Chandrali Bhattacharya, Robert E. Stratford Jr. Conducted experiments: Chandrali Bhattacharya, Andrea Masters, Christine Bach, Anthony L. Sinn, Melissa A. Trowbridge. Performed data analysis: Chandrali Bhattacharya, Andrea Masters, Christine Bach, Robert E. Stratford Jr. Wrote or contributed to the writing of the manuscript: Chandrali Bhattacharya, Robert E. Stratford Jr.

Ethical Approval

The experiments were approved by the Institutional Animal Care and Use Committee (IACUC, Indiana University School of Medicine, protocol number 18091 MD/R, approval date: 10/05/2018). All institutional guidelines for the care of the laboratory animals were followed.

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Bhattacharya, C.S., Masters, A.R., Bach, C. et al. Characterization of the Stereoselective Disposition of Bupropion and Its Metabolites in Rat Plasma and Brain. Eur J Drug Metab Pharmacokinet 48, 171–187 (2023). https://doi.org/10.1007/s13318-023-00817-9

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