Interactions Between Bupropion and Antiretrovirals?

Angela D.M. Kashuba, BScPhm, PharmD, DABCP

Disclosures

June 05, 2001

Question

Many HIV-infected patients receiving antiretroviral therapy are smokers and request prescriptions for bupropion. Apart from the obvious contraindication if patients are on ritonavir, what other potential drug interactions should one be aware of?

David Bradford, MB, BS, FRCS, FACSHP

Response from Angela D.M. Kashuba, BScPhm, PharmD, DABCP

Bupropion is a GlaxoSmithKline product first marketed as an antidepressant under the name Wellbutrin and subsequently marketed as a nonnicotine aid to smoking cessation under the name Zyban.[1]

When evaluating the interaction potential of a drug, multiple pharmacokinetic and pharmacodynamic events need to be considered. Clinically significant pharmacokinetic drug interactions can occur during drug absorption, distribution throughout the body, metabolism, and/or elimination of the drug and its metabolites. Pharmacodynamic drug interactions involve alteration of the pharmacologic response to a drug and can also be clinically significant.

No significant drug interactions have been noted during absorption of bupropion from the gastrointestinal tract. Although taking bupropion with food increases its Cmax and AUC by approximately 11% to 20%, this rate is not deemed to be clinically significant. Similarly, no clinically significant interactions altering the distribution of bupropion have been identified.[1,2]

Unfortunately, few clinical data have been collected on the metabolism of bupropion following administration with other drugs. In vitro experiments have demonstrated that bupropion is extensively metabolized to the pharmacologically active metabolite hydroxybupropion by the cytochrome P450 enzyme 2B6.[3] Because of this, other drugs metabolized by, or affecting the activity of, CYP2B6 may also affect bupropion concentrations. Theoretically, certain drugs that induce multiple P450 enzymes -- carbamazepine, phenobarbital, phenytoin -- may also induce CYP2B6 and may, thus, decrease the concentrations of bupropion and limit its efficacy.[1,4] In addition, drugs that inhibit CYP2B6 activities -- ritonavir, cimetidine, orphenadrine -- may also inhibit bupropion metabolism, increasing the potential for bupropion toxicity. A recent in vitro investigation of protease inhibitors and nonnucleoside reverse transcriptase inhibitors documented strong interaction potentials with ritonavir, nelfinavir, and efavirenz to inhibit bupropion metabolism, and weak interaction potentials with indinavir, saquinavir, amprenavir, delavirdine, and nevirapine.[5]

Although they are not actively metabolized by CYP2D6, bupropion and hydroxybupropion are inhibitors of CYP2D6 enzyme activity. Therefore, coadministration of bupropion with other drugs metabolized by CYP2D6 should be done cautiously to avoid toxicity. These drugs include antidepressants (nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (haloperidol, risperidone, thioridazine), beta-blockers (metoprolol), and antiarrhythmics (propafenone, flecainide). If these drugs are to be used with bupropion, standard doses should be decreased or therapy should be initiated at the low end of the dosing range.

Certain drugs may also increase the potential for bupropion toxicity -- particularly central nervous system effects -- through pharmacodynamic, rather than pharmacokinetic, mechanisms. These interactions include concomitant use of MAO inhibitors (ie, phenelzine), levodopa, and drugs that lower the seizure threshold (antipsychotics, antidepressants, theophylline, systemic steroids, ethanol, abrupt discontinuation of benzodiazepines).

A total of 87% of the dose of bupropion is excreted by the kidneys as metabolites. However, there do not appear to be any significant drug interactions during the renal elimination of bupropion.

Overall, primary drug interaction concerns with bupropion should focus on hepatic metabolism involving CYP2B6 and CYP2D6. Antiretroviral regimens that may increase the potential for bupropion toxicity include those containing ritonavir (including lopinavir/ritonavir), nelfinavir, and efavirenz.

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