Influence of CYP2B6 Pharmacogenetics on Stereoselective Inhibition and Induction of Bupropion Metabolism by Efavirenz in Healthy Volunteers

We investigated the acute and chronic effects of efavirenz, a widely used antiretroviral drug, and CYP2B6 genotypes on the disposition of racemic and stereoisomers of bupropion (BUP) and its active metabolites, 4-hydroxyBUP, threohydroBUP, and erythrohydroBUP. The primary objective of this study was to test how multiple processes unique to the efavirenz-CYP2B6 geno-type interaction influence the extent of efavirenz-mediated drug -drug interaction with the CYP2B6 probe substrate BUP. In a three-phase, sequential, open-label study, healthy volunteers (N 5 53) were administered a single 100 mg oral dose of BUP alone (control phase), with a single 600 mg oral efavirenz dose (inhibition phase), and after 17 days pretreatment with efavirenz (600 mg/d) (induction phase). Compared with the control phase, we show for the first time that efavirenz significantly decreases (by 11%-26%) and chronically increases (by 24%-61%) the ex-posure of hydroxyBUP and its diastereomers, respectively, and the extent of these interactions were CYP2B6 genotype depen-dent. Chronic efavirenz enhances the elimination of racemic BUP and its enantiomers (by 51%-56%) as well as of threo-and erythrohydroBUP and their diastereomers (by 34%-58%), suggesting additional novel mechanisms underlying efavirenz were virenz-BUP SIGNIFICANCE The tabolites. virenzinteraction with BUP. The effects of efavirenz and genotypes were nonstereospecific. In conclusion, acute and chronic admin-istration of efavirenz inhibits and induces CYP2B6 activity. Efa-virenz-BUP interaction is complex, involving time-and CYP2B6 genotype-dependent inhibition and induction of primary and secondary metabolic pathways. Our findings highlight important implications to the safety and efficacy of BUP, study design con-siderations for future efavirenz interactions, and individualized drug therapy based on CYP2B6 genotypes.SIGNIFICANCE STATEMENT The effects of acute and chronic doses of efavirenz on the dis-position of racemic and stereoisomers of bupropion (BUP) and its active metabolites were investigated in healthy volunteers. Efavirenz causes an acute inhibition but chronic induction of CYP2B6 in a genotype-dependent manner. Chronic efavirenz induces BUP reduction and the elimination of BUP active me-tabolites. These data reveal novel mechanisms underlying efa-virenz drug-drug interaction (DDI) with BUP and provide important insights into time-and CYP2B6 genotype-dependent DDIs.