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

Abstract

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 genotype interaction influence the extent of efavirenz-mediated drug-drug interaction (DDI) with the CYP2B6 probe substrate BUP.In a three-phase, sequential, open-label study, healthy volunteers (N=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/day) (induction phase). Compared to the control phase, we show for the first time that efavirenz significantly decreases (by 11-26%) and chronically increases (by 24-61%) the exposure of hydroxyBUP and its diastereomers, respectively, and the extent of these interactions were CYP2B6 genotype dependent. Chronic efavirenz enhances the elimination of racemic BUP and its enantiomers (by 51-56%) as well as of threo-and erythro-hydroBUP and their diastereomers (by 34-58%), suggesting additional novel mechanisms underlying efavirenz interaction with BUP. The effects of efavirenz and genotypes were nonstereospecific. In conclusion, acute and chronic administration of efavirenz inhibits and induces CYP2B6 activity. Efavirenz-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 considerations for This article has not been copyedited and formatted. The final version may differ from this version.

Pharmacogenetic Influence on Stereoselective Steady-State Disposition of Bupropion

“…The frequency of CYP2B6 diplotypes in the cohort ( 1 for plasma and in Table 2 for urine. Disposition was highly stereoselective, as observed previously for single-dose (Kharasch et al, 2008;Masters et al, 2016;Kharasch and Crafford, 2019;Gufford et al, 2022) and steady-state (Kharasch et al, 2020) CYP2B6*6 (516G>T, rs3745274 and 785A>G, rs2279343) is the most common and most extensively studied CYP2B6 variant, and eliciting lower protein expression due to the 516G>T single nucleotide variant causing an amino acid change and aberrant splicing (Hofmann et al, 2008). The 516G>T single nucleotide variant is however also found in numerous other CYP2B6 alleles, and is considered a canonical decreased function allele.…”

“…Metabolism in vitro to the more recently identified metabolite 4'-hydroxybupropion, and secondary metabolites 4'-hydroxy-erythrohydrobupropion and 4'-hydroxy-threohydrobupropion is also stereoselective (Sager et al, 2016a;Sager et al, 2016b). Prior human in vivo investigations showed that single-dose (Kharasch et al, 2008;Masters et al, 2016;Gufford et al, 2022) and steady-state (Kharasch et al, 2020) bupropion disposition in humans is also stereoselective. The clinical importance of metabolite formation 6 has been recognized for smoking cessation and antidepressant therapy (Lee et al, 2007;Zhu et al, 2012;Laib et al, 2014).…”

“…CYP2B6 polymorphisms influence human in vitro bupropion hydroxylation (Wang et al, 2020). CYP2B6 polymorphisms influence human in vivo hydroxylation of single-dose bupropion racemate (Kirchheiner et al, 2003;Chung et al, 2011;Gao et al, 2016;Lv et al, 2016;Ma et al, 2018;Eum et al, 2022), and single-dose bupropion enantiomers (Kharasch and Crafford, 2019;Gufford et al, 2022).…”

Expression of CYP2B6 Enzyme in Human Liver Tissue of HIV and HCV Patients

“…It is important to note that most of the studies that analyze CYP2B6 activity were conducted using some kind of surrogate endpoint, such as efavirenz plasma concentration, or were performed on tissues such as peripheral blood cells or healthy donor hepatocytes cell culture [ 22 , 24 , 26 ]. One of the few studies performed on human liver tissue samples in a population of HCV mono-infected patients by Drozdzik et al showed that there was down-regulation of a couple of CYP enzymes, but the level of CYP2B6 remained unchanged [ 27 ].…”

In vitro Assessment of the Effects of Silybin on CYP2B6-mediated Metabolism

“…We chose bupropion, a CYP2B6-sensitive probe substrate 11 , to examine the CYP2B6 activity in vitro . The objective of this study was to determine how much silybin inhibits CYP2B6 activity and protein expression in an in vitro study.…”