Bupropion is metabolized extensively in humans by oxidative and reductive processes. CYP2B6 mediates oxidation of bupropion to hydroxybupropion, but the enzyme(s) catalyzing carbonyl reduction of bupropion to erythro- and threohydrobupropion in human liver is unknown. The objective of this study was to examine the enzyme kinetics of bupropion reduction in human liver. In human liver cytosol, the reduction of bupropion to erythro-and threohydrobupropion was NADPH dependent with Cl(int) values of 0.08 and 0.60 µL·min(-1)mg(-1) protein, respectively. Bupropion reduction in liver microsomes was also NADPH dependent with Cl(int) values of 10.4 and 280 µL·min(-1)mg(-1) protein, respectively. Formation of erythro-and threohydrobupropion in microsomes exceeded that in cytosol by 70 and 170 fold, respectively. Menadione, an inhibitor of cytosolic carbonyl reducing enzymes (e.g. CBRs), inhibited erythro-and threohydrobupropion formation in cytosol with IC(50) of 30 and 54 µM, respectively. In microsomes 18β-glycyrrhetinic acid, an inhibitor of microsomal carbonyl reductases (e.g. 11β-HSDs), inhibited their formation with IC(50) of 25 and 26 nM, respectively. Our findings, in agreement with recent human placental studies, show that carbonyl reducing enzymes in hepatic microsomes are significant players in bupropion reduction. Contrary to past studies, we found that threohydrobupropion (not hydroxybupropion) is the major microsomal generated hepatic metabolite of bupropion.

Bupropion is an atypical antidepressant that is biotransformed in humans to its major active metabolite hydroxybupropion by cytochrome P450 2B6 (CYP2B6). Co-administration of bupropion with an inhibitor of CYP2B6 can result in a serious drug interaction, leading to bupropion related adverse effects (e.g. seizures). The antiplatelet agent ticlopidine has been identified as a potent in vitro inhibitor of bupropion hydroxylation, however it is unknown if it interacts in vivo in rodents. In this study we investigated the potential pharmacokinetic (PK) drug interaction between bupropion and ticlopidine in mice. Using a destructive sampling design, male CF-1 mice were administered ticlopidine 1.0 mg/kg daily for 5 d, followed by single-dose bupropion 50 mg/kg. Bupropion and hydroxybupropion levels were measured by HPLC-UV in plasma and brain tissues at 30, 60, 90, 120 and 180 min post-dose, and compared between treatment groups. There was a strong trend in both plasma and brain data towards greater bupropion levels and smaller hydroxybupropion levels in ticlopidine treated mice. Analysis of variance indicated statistical differences (pϽ Ͻ0.05) at many time points. The variance associated with the area under the curve was calculated using Bailer's method and significant differences were found between treatment groups. Taken together, the concentration time point statistical analysis followed by PK modeling demonstrate a significant PK drug interaction between bupropion and ticlopidine. To our knowledge, this is the first study to document an in vivo drug interaction between these drugs in mice. Our findings support future in vivo drug interaction studies in mice between bupropion and CYP2B6 inhibitors.

Sertraline potently inhibits cytochrome P450 2B6 (CYP2B6) in vitro. Bupropion is commonly co-prescribed with sertraline and is exclusively metabolized by CYP2B6 to its major active metabolite hydroxybupropion. Putatively the co-administration of bupropion and sertraline could lead to a significant pharmacokinetic drug-drug interaction. The aim of this study was to evaluate a possible drug interaction between these drugs in mice. To study this male CF-1 mice were administered sertraline 5 mg/kg once daily for 6 days, followed by a single dose of bupropion 50 mg/kg on the seventh study day. Plasma and brain samples were collected post-bupropion dose for measurement of bupropion and hydroxybupropion levels on HPLC. Pharmacokinetic parameters for bupropion and hydroxybupropion were calculated using noncompartmental analysis and the variance in AUC of each was computed using Bailer's analysis. We found that mice pretreated with sertraline exhibited a small elevation in bupropion metabolism. This was substantiated by Bailer's analysis which indicated that in the presence of sertraline, both plasma and brain bupropion exposure were significantly (p < 0.05) decreased, while plasma hydroxybupropion exposure was significantly (p < 0.05) increased. Also the plasma hydroxybupropion-to-bupropion ratio of AUC was increased by 27% in sertraline treated mice, indicative of increased CYP2B activity. This is the first study, to our knowledge, that reports a mild pharmacokinetic drug-drug interaction between bupropion and sertraline in mice. However, it is unknown whether these quantitative changes in enzyme activity and consequent drug exposure would equate to significant pharmacodynamic changes (e.g., perturbations in brain neurotransmitter levels) observed in the clinic.

Bupropion is a popular antidepressant that is also prescribed in the management of smoking cessation. In humans, bupropion is predominantly metabolized to its active metabolite hydroxybupropion by CYP2B6. Inhibitors of CYP2B6 have the potential to decrease the clearance of bupropion, leading to adverse drug toxicity. We sought to develop a sensitive HPLC‐UV assay to quantify plasma and brain concentrations of bupropion and hydroxybupropion; and apply the assay to assess in vivo pharmacokinetic (PK) drug‐drug interaction (DDI) studies between bupropion and potent CYP2B6 inhibitors. Tissue extraction followed by HPLC‐UV detected timolol (IS), hydroxybupropion and bupropion at 6, 11 and 36 minutes, respectively. The LOD for both compounds was 6.0 ng/ml, and the intra‐day and inter‐day coefficients of variation was ±12% in plasma and ±15% in whole brain tissue. We then utilized this novel technique to evaluate the PK of bupropion and hydroxybupropion following repeated administration of the known CYP2B6 inhibitor ticlopidine (5 mg/kg daily x 5 days) in CF‐1 mice. Ticlopidine increased the plasma area under the concentration curve (AUC) of bupropion (2.0‐fold, p< 0.01) and decreased the plasma AUC of hydroxybupropion (1.2‐fold;p< 0.05). In whole brain tissue, ticlopidine increased the AUC of bupropion (1.3‐fold;p> 0.05)and decreased the AUC of hydroxybupropion (2.0‐fold;p< 0.001). In summary, we have developed a sensitive HPLC assay and suitable rodent model to evaluate in vivo PK DDI between bupropion and CYP2B6 inhibitors. Support: Drake Univ COPHS Intramural Research Grants.