Effects of Hydroxymetabolites of Bupropion on Nicotine Dependence Behavior in Mice

Damaj, M. Imad; Grabus, Sheri D.; Navarro, Hernán A.; Vann, Robert E.; Warner, Jonathan A.; King, Lindsey S.; Wiley, Jenny L.; Blough, Bruce E.; Lukas, Ronald J.; Carroll, F. Ivy

doi:10.1124/jpet.110.166850

Cited by 42 publications

(48 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Bupropion is used clinically to promote smoking cessation. Animal and human data suggest that bupropion's ability to promote smoking cessation is at least partially mediated by its major plasma metabolite OH-BUP (Damaj et al, 2010;Zhu et al, 2012). At steady state, plasma OH-BUP levels are 10-20 times higher than plasma bupropion levels, and OH-BUP has higher affinity for the a4b2 nicotinic acetylcholine receptors than bupropion (Damaj et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

“…Among these metabolites, OH-BUP had the highest steady-state plasma levels, and has been shown to be pharmacologically active ( Fig. 1) (Damaj et al, 2004(Damaj et al, , 2010Zhu et al, 2012;Benowitz et al, 2013). Higher levels of OH-BUP, but not bupropion, were associated with greater rates of smoking cessation in smokers receiving bupropion treatment (Zhu et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

See 1 more Smart Citation

Gene Variants in CYP2C19 Are Associated with Altered In Vivo Bupropion Pharmacokinetics but Not Bupropion-Assisted Smoking Cessation Outcomes

et al. 2014

View full text Add to dashboard Cite

Bupropion is used clinically to treat depression and to promote smoking cessation. It is metabolized by CYP2B6 to its active metabolite hydroxybupropion, yet alterations in CYP2B6 activity have little impact on bupropion plasma levels. Furthermore, less than 10% of a bupropion dose is excreted as urinary bupropion and its characterized metabolites hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, suggesting that alternative metabolic pathways may exist. In vitro data suggested CYP2C19 could metabolize bupropion. The current study investigated the impact of functional CYP2C19 genetic variants on bupropion pharmacokinetics and treatment outcomes. In 42 healthy volunteers, CYP2C19*2 (a reduced activity allele) was associated with higher bupropion area under the plasma concentration-time curve (AUC), but similar hydroxybupropion AUC. The mean bupropion AUC was 771 versus 670 hours×ng/ml in individuals with and without CYP2C19*2, respectively (P = 0.017). CYP2C19*2 was also associated with higher threohydrobupropion and erythrohydrobupropion AUC (P < 0.005). Adjusting for CYP2B6 genotype did not alter these associations, and CYP2C19 variants did not alter the utility of the hydroxybupropion/bupropion ratio as a measure of CYP2B6 activity. Finally, in a clinical trial of 540 smokers, CYP2C19 genotype was not associated with smoking cessation outcomes, supporting the hypothesis that bupropion response is mediated by hydroxybupropion, which is not altered by CYP2C19. In conclusion, our study reports the first in vivo evidence that reduced CYP2C19 activity significantly increases the steady-state exposure to bupropion and its reductive metabolites threohydrobupropion and erythrohydrobupropion. These pharmacokinetic changes were not associated with differences in bupropion's ability to promote smoking cessation in smokers, but may influence the side effects and toxicity associated with bupropion.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Gene Variants in CYP2C19 Are Associated with Altered In Vivo Bupropion Pharmacokinetics but Not Bupropion-Assisted Smoking Cessation Outcomes

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Different metabolites of bupropion have significant impact on its efficacy, since these metabolites have 25-50% potency compared with bupropion on the basis of antidepressant screening tests in an animal model (Bondarev et al, 2003;Damaj et al, 2004). In addition, the plasma levels of hydroxybupropion are 5-to 10-fold higher than the parent drug bupropion after oral administration of bupropion HCl (Bondarev et al, 2003;Damaj et al, 2004;Jefferson et al, 2005;Damaj et al, 2010;Zhu et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

Metabolism of Bupropion by Carbonyl Reductases in Liver and Intestine

et al. 2015

View full text Add to dashboard Cite

Bupropion's metabolism and the formation of hydroxybupropion in the liver by cytochrome P450 2B6 (CYP2B6) has been extensively studied; however, the metabolism and formation of erythro/threohydrobupropion in the liver and intestine by carbonyl reductases (CR) has not been well characterized. The purpose of this investigation was to compare the relative contribution of the two metabolism pathways of bupropion (by CYP2B6 and CR) in the subcellular fractions of liver and intestine and to identify the CRs responsible for erythro/threohydrobupropion formation in the liver and the intestine. The results showed that the liver microsome generated the highest amount of hydroxybupropion (Vmax = 131 pmol/min per milligram, Km = 87 μM). In addition, liver microsome and S9 fractions formed similar levels of threohydrobupropion by CR (Vmax = 98-99 pmol/min per milligram and Km = 186-265 μM). Interestingly, the liver has similar capability to form hydroxybupropion (by CYP2B6) and threohydrobupropion (by CR). In contrast, none of the intestinal fractions generate hydroxybupropion, suggesting that the intestine does not have CYP2B6 available for metabolism of bupropion. However, intestinal S9 fraction formed threohydrobupropion to the extent of 25% of the amount of threohydrobupropion formed by liver S9 fraction. Enzyme inhibition and Western blots identified that 11β-dehydrogenase isozyme 1 in the liver microsome fraction is mainly responsible for the formation of threohydrobupropion, and in the intestine AKR7 may be responsible for the same metabolite formation. These quantitative comparisons of bupropion metabolism by CR in the liver and intestine may provide new insight into its efficacy and side effects with respect to these metabolites.

show abstract

“…BUP is 4-hydroxylated by CYP2B6 to OHBUP (Faucette et al, 2000;Hesse et al, 2000;Benowitz et al, 2013), whereas the reduction of BUP by 11b-hydroxysteroid dehydrogenase 1 and other carbonyl reductases (Meyer et al, 2013;Connarn et al, 2015) forms two amino alcohol stereoisomers, THRHBUP and ERYHBUP. OHBUP, THRHBUP, and ERYHBUP exhibit pharmacological activity in preclinical models (Martin et al, 1990;Bondarev et al, 2003;Damaj et al, 2004Damaj et al, , 2010 and may mediate BUP-induced seizures (Silverstone et al, 2008). In humans, these metabolites are believed to be responsible for BUP treatment outcomes (Daviss et al, 2006;Dwoskin et al, 2006;Lee et al, 2007;Zhu et al, 2012;Laib et al, 2014) and for clinically observed DDIs between BUP and CYP2D6 substrates (Reese et al, 2008;Parkinson et al, 2010;Yeung et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

Masters

Gufford

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug-drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (n 5 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography-tandem mass spectrometry assays. Time-dependent, elimination rate-limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and C max ratios were approximately 35, 6, 3, and 0.5 for (2R,3R)-/(2S,3S)-hydroxybupropion, R-/S-bupropion, (1S,2R)-/(1R,2S)-erythrohydrobupropion, and (1R,2R)-/(1S,2S)-threohydrobupropion, respectively. The R-/S-bupropion and (1R,2R)-/(1S,2S)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of S-versus R-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2S,3S)-hydroxybupropion was almost 10-fold higher than that of (2R,3R)-hydroxybupropion. The prediction of steadystate pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300-312 hours) from 185 to 37,447 nM×h] and elimination [terminal half-life of approximately 7-46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion's effects and DDIs with CYP2D6.

show abstract

Effects of Hydroxymetabolites of Bupropion on Nicotine Dependence Behavior in Mice

Cited by 42 publications

References 24 publications

Gene Variants in CYP2C19 Are Associated with Altered In Vivo Bupropion Pharmacokinetics but Not Bupropion-Assisted Smoking Cessation Outcomes

Gene Variants in CYP2C19 Are Associated with Altered In Vivo Bupropion Pharmacokinetics but Not Bupropion-Assisted Smoking Cessation Outcomes

Metabolism of Bupropion by Carbonyl Reductases in Liver and Intestine

Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

Contact Info

Product

Resources

About