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II. The Role of Metabolites in Clinical Outcome

Robert N. Golden, MD; C. Lindsay DeVane, PharmD; S. Casey Laizure, PharmD; Matthew V. Rudorfer, MD; Michael A. Sherer, MD; William Z. Potter, MD, PhD

Arch Gen Psychiatry. 1988;45(2):145-149.

Abstract
• We studied the steady-state pharmacokinetics of bupropion hydrochloride, a unicyclic aminoketone antidepressant, in depressed patients. The metabolites hydroxybupropion (HB), threohydrobupropion, and erythrohydrobupropion predominated over the parent compound in plasma and cerebrospinal fluid at steady state. Plasma concentrations of each metabolite correlated with cerebrospinal fluid concentrations. Higher plasma metabolite concentrations were associated with poor clinical outcome. This relationship was most striking with HB; plasma HB levels were greater than 1250 ng/mL in all five nonresponders and less than 1200 ng/mL in all seven responders. Plasma HB levels correlated with postreatment plasma homovanillic acid levels. High levels of bupropion metabolites may be associated with poor clinical outcome due to toxic effects involving dopaminergic systems. Alternatively, a curvilinear dose-response relationship may exist for bupropion metabolites. Future studies should explore the clinical utility of plasma metabolite measurements in enhancing the efficacy of treatment with bupropion.

Author Affiliations
From the Section on Clinical Pharmacology, Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Md (Drs Golden, Rudorfer, Sherer, and Potter); and the Department of Pharmacy Practice, College of Pharmacy (Drs DeVane and Laizure) and the Department of Psychiatry, College of Medicine (Dr DeVane), University of Florida, Gainesville. Dr Golden is now with the University of North Carolina School of Medicine, Chapel Hill.

Footnotes
Accepted for publication Aug 19, 1985.

Read in part at the 40th annual meeting of the Society of Biological Psychiatry, Dallas, May 17, 1985; and at the 138th annual meeting of the American Psychiatric Association, Dallas, May 22, 1985.

Reprint requests to Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27514 (Dr Golden).

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