Dataset Information

Transport of Bupropion and its Metabolites by the Model CHO and HEK293 Cell Lines.

ABSTRACT: BACKGROUND:Bupropion (BUP) is widely used as an antidepressant and smoking cessation aid. There are three major pharmacologically active metabolites of BUP, Erythrohydrobupropion (EB), Hydroxybupropion (OHB) and Threohydrobupropion (TB). At present, the mechanisms underlying the overall disposition and systemic clearance of BUP and its metabolites have not been well understood, and the role of transporters has not been studied. OBJECTIVE:The goal of this study was to investigate whether BUP and its active metabolites are substrates of the major hepatic uptake and efflux transporters. METHOD:CHO or HEK293 cell lines or plasma membrane vesicles that overexpress OATP1B1, OATP1B3, OATP2B1, OATP4A1, OCT1, BCRP, MRP2 or P-gp were used in cellular or vesicle uptake and inhibition assays. Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) was used to quantify transport activity. RESULTS:BUP and its major active metabolites were actively transported into the CHO or HEK293 cells overexpressing OATP1B1, OATP1B3 or OATP2B1; however, such cellular active uptake could not be inhibited at all by prototypical inhibitors of any of the OATP transporters. These compounds were not transported by OCT1, BCRP, MRP2 or P-gp either. These results suggest that the major known hepatic transporters likely play a minor role in the overall disposition and systemic clearance of BUP and its active metabolites in humans. We also demonstrated that BUP and its metabolites were not transported by OATP4A1, an uptake transporter on the apical membrane of placental syncytiotrophoblasts, suggesting that OATP4A1 is not responsible for the transfer of BUP and its metabolites from the maternal blood to the fetal compartment across the placental barrier in pregnant women. CONCLUSION:BUP and metabolites are not substrates of the major hepatic transporters tested and thus these hepatic transporters likely do not play a role in the overall disposition of the drug. Our results also suggest that caution should be taken when using the model CHO and HEK293 cell lines to evaluate potential roles of transporters in drug disposition.

SUBMITTER: Han LW

PROVIDER: S-EPMC7451048 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Transport of Bupropion and its Metabolites by the Model CHO and HEK293 Cell Lines.

Han Lyrialle W LW Gao Chunying C Zhang Yuchen Y Wang Joanne J Mao Qingcheng Q

Drug metabolism letters 20190101 1

<h4>Background</h4>Bupropion (BUP) is widely used as an antidepressant and smoking cessation aid. There are three major pharmacologically active metabolites of BUP, Erythrohydrobupropion (EB), Hydroxybupropion (OHB) and Threohydrobupropion (TB). At present, the mechanisms underlying the overall disposition and systemic clearance of BUP and its metabolites have not been well understood, and the role of transporters has not been studied.<h4>Objective</h4>The goal of this study was to investigate w ...[more]

PMID: 30488806

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Project description:Bupropion is a widely used antidepressant and smoking cessation aid in addition to being one of two US Food and Drug Administration-recommended probe substrates for evaluation of cytochrome P450 2B6 activity. Racemic bupropion undergoes oxidative and reductive metabolism, producing a complex profile of pharmacologically active metabolites with relatively little known about the mechanisms underlying their elimination. A liquid chromatography-tandem mass spectrometry assay was developed to simultaneously separate and detect glucuronide metabolites of (R,R)- and (S,S)-hydroxybupropion, (R,R)- and (S,S)-hydrobupropion (threo) and (S,R)- and (R,S)-hydrobupropion (erythro), in human urine and liver subcellular fractions to begin exploring mechanisms underlying enantioselective metabolism and elimination of bupropion metabolites. Human liver microsomal data revealed marked glucuronidation stereoselectivity [Cl(int), 11.4 versus 4.3 µl/min per milligram for the formation of (R,R)- and (S,S)-hydroxybupropion glucuronide; and Cl(max), 7.7 versus 1.1 µl/min per milligram for the formation of (R,R)- and (S,S)-hydrobupropion glucuronide], in concurrence with observed enantioselective urinary elimination of bupropion glucuronide conjugates. Approximately 10% of the administered bupropion dose was recovered in the urine as metabolites with glucuronide metabolites, accounting for approximately 40%, 15%, and 7% of the total excreted hydroxybupropion, erythro-hydrobupropion, and threo-hydrobupropion, respectively. Elimination pathways were further characterized using an expressed UDP-glucuronosyl transferase (UGT) panel with bupropion enantiomers (both individual and racemic) as substrates. UGT2B7 catalyzed the stereoselective formation of glucuronides of hydroxybupropion, (S,S)-hydrobupropion, (S,R)- and (R,S)-hydrobupropion; UGT1A9 catalyzed the formation of (R,R)-hydrobupropion glucuronide. These data systematically describe the metabolic pathways underlying bupropion metabolite disposition and significantly expand our knowledge of potential contributors to the interindividual and intraindividual variability in therapeutic and toxic effects of bupropion in humans.

Dataset Information

Transport of Bupropion and its Metabolites by the Model CHO and HEK293 Cell Lines.

Publications

Transport of Bupropion and its Metabolites by the Model CHO and HEK293 Cell Lines.

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