Drug Interaction Study between Bupropion and Ticlopidine in Male CF-1 Mice

Abstract

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.

Deletion of 30 Murine Cytochrome P450 Genes Results In Viable Mice With Compromised Drug Metabolism

“…4). Bupropion hydroxylation, a marker of Cyp2b (Molnari et al, 2011), was increased (40-fold) in the absence of the three Cyp gene clusters, which could be accounted for by the induction of Cyp2b10 protein (Fig. 2C).…”

Effects of sertraline on the pharmacokinetics of bupropion and its major metabolite, hydroxybupropion, in mice

“…Recently, our laboratory confirmed these in vitro and in vivo findings by demonstrating that ticlopidine significantly inhibits bupropion metabolism in mice (Molnari et al 2011). We showed that CF-1 mice pretreated with ticlopidine exhibited a statistically significant increase in the area under the concentration time curve (AUC) of bupropion in both plasma and brain tissues, whereas the AUC of bupropion's metabolite hydroxybupropion was reduced (Molnari et al 2011).…”

“…Mice were chosen as a representative animal species for this project since: (a) in comparison to rats, the conversion of bupropion to its major active metabolite hydroxybupropion in mice is more closely related to humans (Suckow et al 1986); (b) others have successfully used CF-1 mice to study drug interactions between bupropion and other psychotropic agents (Wang et al 2006); and (c) our previous studies used CF-1 mice to demonstrate a PK drug-drug interaction between bupropion and prototypical CYP2B6 inhibitor ticlopidine (Molnari et al 2011). Male CF-1 mice (30-35 g) aged 3 months were obtained from Charles River Laboratories (Wilmington, MA) and individually housed in the Drake University Animal Care facility under 12 h light-dark cycles with free access to food and water.…”

“…bupropion (50 mg/kg, calculated as free-base) ± sertraline (5 mg/kg; calculated as free-base), then sacrificed by CO 2 asphyxiation at 5, 10, 30, 60, 90, 120, 180, 240, 300, and 360 min post-dose. The selection of the bupropion dose was based on previous bupropion drug interaction studies (Molnari et al 2011;Wang et al 2006) and the following criteria: (a) the effective bupropion dose and measured plasma concentrations of bupropion and hydroxybupropion are comparable with human clinical situations; and (b) the lowest concentration of compounds exceeds the limit of quantitation of the HPLC assay. Immediately after sacrificed, blood was collected via heart puncture using heparinized syringes and centrifuged at 1,8009g for 15 min.…”

“…Using our previous methodology, in which we developed a sensitive method to demonstrate a drug interaction between prototypical CYP2B6 inhibitor ticlopidine and bupropion (Molnari et al 2011), we sought to investigate the potential PK drug-drug interaction between bupropion and sertraline in mice.…”