Jillissa C. Molnari

Drake University

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Alan L. Myers

The University of Texas Health Science Center at Houston

Bryant Moeller

Drake University

Hazem E. Hassan

Regeneron (United States)

Cooperative Institutions

Drake University

University of Maryland, Baltimore

Helwan University

University of Minnesota

The University of Texas Health Science Center at Houston

The University of Texas MD Anderson Cancer Center

University of Pennsylvania

The University of Texas at Austin

John Wiley & Sons (United States)

Bristol-Myers Squibb (United States)

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Carbonyl Reduction of Bupropion in Human Liver Cytosol

The FASEB Journal (2011)

Jillissa C. Molnari

Bupropion

Human liver

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

European Journal of Drug Metabolism and Pharmacokinetics (2011)

Jillissa C. Molnari Hazem E. Hassan Alan L. Myers

Bupropion

Sertraline

CYP2B6

Active metabolite

10.1007/s13318-011-0065-6

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Citations (13)

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

Biological and Pharmaceutical Bulletin (2011)

Jillissa C. Molnari Hazem E. Hassan Bryant Moeller Alan L. Myers

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 (p<0.05) 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.

Bupropion

Ticlopidine

CYP2B6

Tacrine

Active metabolite

10.1248/bpb.34.447

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Citations (10)

HPLC‐UV analysis of bupropion and hydroxybupropion: Application to in vivo pharmacokinetic drug‐drug interaction studies between bupropion and potent CYP2B6 inhibitors

The FASEB Journal (2010)

Alan L. Myers Jillissa C. Molnari Bryant Moeller Alan L. Myers

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.

Bupropion

CYP2B6

Active metabolite

Tacrine

10.1096/fasebj.24.1_supplement.967.9

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Citations (1)

HPLC with Fluorometric Detection of Brain Catecholamines in a Pharmacodynamic Study Between Two Popular Antidepressants

Bryant Moeller Jillissa C. Molnari

Pharmacodynamics

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Carbonyl reduction of bupropion in human liver

Xenobiotica (2012)

Jillissa C. Molnari Alan L. Myers

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.

Bupropion

CYP2B6

Human liver

Liver enzyme

10.3109/00498254.2011.643416

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Citations (25)