Dr. Bob's Psychopharmacology Tips Biological Therapies in Psychiatry Alan J. Gelenberg, M.D.

Bupropion's Metabolism

Doctors are becoming increasingly concerned with the pharmacokinetics of drugs, as they can predict potential interactions and other problems. We know a fair amount about the metabolism of most of the newer antidepressants, but comparatively little about the metabolism of bupropion (Wellbutrin). Several recent reports are interesting in this regard.

Pollock and others studied the pharmacokinetics of bupropion in six patients. (1) Their data suggest bupropion is not metabolized by the 2D6 isoenzyme of the P450 hepatic system. Three of the patients, however, who had genetically low levels of 2D6 activity ("poor metabolizers"), had high plasma levels of the active metabolite hydroxybupropion, suggesting that the metabolite may be degraded by 2D6. Since two commonly used serotonin-selective reuptake inhibitors (SSRIs) -- fluoxetine (Prozac) and paroxetine (Paxil) -- are potent inhibitors of 2D6, it is likely that coadministering these agents with bupropion also would lead to elevated levels of hydroxybupropion. An earlier report from Golden and colleagues found that higher plasma levels of hydroxybupropion were correlated with poor clinical antidepressant response. (2) Thus, patients with genetically or drug-induced low 2D6 levels may have a less favorable clinical outcome.

Sweet et al studied the kinetics of bupropion in 6 elderly depressed patients. (3) They found reduced clearance and about a 25% increase in steady state concentration of bupropion compared to comparable doses in younger patients. In addition, levels of hydroxybupropion and other metabolites showed an even greater rise. The authors recommend lower bupropion doses in the elderly than in younger patients.

Additional clues to bupropion's metabolism come from a study by Ketter and collaborators, who examined the effects of coadministered carbamazepine (Tegretol and others) and valproate (Depakene) on the pharmacokinetics of bupropion. (4) Carbamazepine but not valproate decreased bupropion levels, presumably by its well known ability to induce enzymes. This suggests that the first step in bupropion's metabolism may involve the 3A4 isoenzyme of P450. Of further interest, both carbamazepine and valproate increased hydroxybupropion concentrations.

To summarize, it appears that therapeutic response to bupropion may be diminished in patients with high levels of the hydroxy metabolite. Hydroxybupropion levels are likely to increase if bupropion is coadministered with an SSRI, valproate, or carbamazepine. They may also be elevated in the elderly. A conservative strategy would be to titrate bupropion dosage even more gradually than usual in the elderly and in patients taking one of these agents (or other 2D6 inhibitors).

With its dose-related liability to cause seizures and a possibly unique mechanism of action, perhaps involving dopamine, bupropion is different from other antidepressants. Unlike SSRIs, it does not usually cause sexual side effects. In fact, patients who have developed sexual dysfunction on SSRIs and are switched to bupropion show improvement in sexual functioning. (5) Some doctors have even tried adding bupropion to an SSRI regimen to combat drug-induced sexual effects. (6) As these studies point out, this combination may decrease antidepressant response, so bupropion should be added slowly and the patient observed closely for a recurrence of depressive symptoms.

1. Pollock BG, Sweet RA, Kirshner M, Reynolds CF III: Bupropion plasma levels and CYP2D6 phenotype. Ther Drug Monit 1996; 18: 581-585.
2. Golden RN, DeVane CL, Laizure SC, Rudorfer MV, Sherer MA, Potter WZ: Bupropion in depression: II. The role of metabolites in clinical outcome. Arch Gen Psychiatry 1988; 45: 145-149.
3. Sweet RA, Pollock BG, Kirshner M, Wright B, Altieri LP, DeVane CL: Pharmacokinetics of single- and multiple-dose bupropion in elderly patients with depression. J Clin Pharmacol 1995; 35: 876-884.
4. Ketter TA, Jenkins JB, Schroeder DH, Pazzaglia PJ, Marangell LB, George MS, Callahan AM, Hinton ML, Chao J, Post RM: Carbamazepine but not valproate induces bupropion metabolism. J Clin Psychopharmacol 1995; 15: 327-333.
5. Walker PW, Cole JO, Gardner EA, Hughes AR, Johnston JA, Batey SR, Lineberry CG: Improvement in fluoxetine-associated sexual dysfunction in patients switched to bupropion. J Clin Psychiatry 1993; 54: 459-465.
6. Labbate LA, Pollack MH: Treatment of fluoxetine-induced sexual dysfunction with bupropion: A case report. Ann Clin Psychiatry 1994; 6: 13-15.

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Original article copyright 1996 Biological Therapies in Psychiatry.
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