Bupropion for major depressive disorder: Pharmacokinetic and formulation considerations

Background: Major depressive disorder (MDD) is a common psychiatric condition, with 6.6% of the adult population in the United States experiencing a major depressive episode during any given year. Depressed patients must receive adequate treatment to maximize the likelihood of clinical success. Bupropion hydrochloride, a noradrenergic/dopamincrgic antidepressant, is available in 3 oral formulations: immediate release (IR) (given TID), sustained release (SR) (given BID), and extended release (XL) (given QD). Understanding the pharmacokinetic (PK) properties and formulations of bupropion can help optimize clinical use. Objectives: The alms of this article were to provide a review of the PK properties of bupropion and identify its various formulations and clinical applications to help optimize treatment of MDD. Methods: In this review, data concerning PK trials/reports were collected from articles identified using a PubMed search. The search was conducted without date limitations and using the search terms bupropion, bupropion SR, bupropion XL, bupropion pbarmaco-kinetics, bupropion metabolism, and bupropion drug interactions. Additional reports were selected from references that appeared in articles identified in the original search. In addition, data from studies summarized in product information and labeling were obtained. All available information, concentrating on studies in humans, pertinent to bupropion PK properties and/or formulations was included. Results: Bupropion is extensively metabolized by the liver (t(1/2), similar to 21 hours). Hydroxybupropion, the primary active metabolite (t(1/2), similar to 20 hours), is formed by cytochrome P450 (CYP) 2B6. At steady state, C-max of hydroxybupropion is 4- to 7-fold higher, and the AUC is similar to 10-fold greater, compared with those of the parent drug. Threohydrobupropion and erythrohydrobupropion (mean [SD] t(1/2) values, similar to 37 [13] and similar to 33 [10] hours, respectively), the other active metabolites of bupropion, are formed via nonmicrosomal pathways. Relative to bupropion, the C-max values are similar to 5-fold greater for threohydrobupropion and similar for erythrohydrobupropion. Based on a mouse antitetrabenazine model, hydroxybupropion is similar to 50% as active as bupropion, and threohydrobupropion and erythrohydrobupropion are similar to 20% as active as bupropion. Bupropion lowers the seizure threshold and, therefore, concurrent administration with other agents that lower the seizure threshold should be undertaken cantiously. Potential interactions with other agents that are metabolized by CYP2B6 should be considered. In addition, bupropion inhibits CYP2D6 and may reduce clearance of agents metabolized by this enzyme. Absorption of the XL formulation is prolonged compared with the IR and SR formulations (T-max, similar to 5 hours vs similar to 1.5 and similar to 3 hours, respectively). Bupropion is dosed without regard to food. Conclusions: Understanding the PK profile and formulations of bupropion can help optimize clinical use. Bupropion is metabolized extensively, resulting in 3 active metabolites. This metabolic profile, various patient factors (eg, age, medical illnesses), and potential drug interactions should be considered when prescribing bupropion. The 3 formulations-bupropion, bupropion SR, and buproplon XL-are bioequivalent and offer options to optimize treatment for patients with MDD.