Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation

Palovaara, Sanna; Pelkonen, Olavi; Uusitalo, Jouko; Lundgren, Stephan; Laine, Kari

doi:10.1016/s0009-9236(03)00202-9

Cited by 76 publications

(76 citation statements)

References 29 publications

(35 reference statements)

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“…Pharmacological administration of cortisone and prednisone, high endogenous cortisone during stress, or the use of 11b-HSD1 inhibitors (currently in development to treat metabolic syndrome and other diseases Anagnostis et al, 2013;Gathercole et al, 2013;Luo et al, 2013;Tiganescu et al, 2013;Venier et al, 2013) are likely to result in higher hydroxybupropion levels, which will necessitate a readjustment of the therapeutic dose of bupropion. Subjects receiving hormone replacement therapy, which leads to inhibition of CYP2B6, had diminished hydroxybupropion levels and increased erythro-and threohydrobupropion levels (Palovaara et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Formation of Threohydrobupropion from Bupropion Is Dependent on 11β-Hydroxysteroid Dehydrogenase 1

et al. 2013

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Bupropion is widely used for treatment of depression and as a smoking-cessation drug. Despite more than 20 years of therapeutic use, its metabolism is not fully understood. While CYP2B6 is known to form hydroxybupropion, the enzyme(s) generating erythro-and threohydrobupropion have long remained unclear. Previous experiments using microsomal preparations and the nonspecific inhibitor glycyrrhetinic acid suggested a role for 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1) in the formation of both erythro-and threohydrobupropion. 11b-HSD1 catalyzes the conversion of inactive glucocorticoids (cortisone, prednisone) to their active forms (cortisol, prednisolone). Moreover, it accepts several other substrates. Here, we used for the first time recombinant 11b-HSD1 to assess its role in the carbonyl reduction of bupropion. Furthermore, we applied human, rat, and mouse liver microsomes and a selective inhibitor to characterize species-specific differences and to estimate the relative contribution of 11b-HSD1 to bupropion metabolism. The results revealed 11b-HSD1 as the major enzyme responsible for threohydrobupropion formation. The reaction was stereoselective and no erythrohydrobupropion was formed. Human liver microsomes showed 10 and 80 times higher activity than rat and mouse liver microsomes, respectively. The formation of erythrohydrobupropion was not altered in experiments with microsomes from 11b-HSD1-deficient mice or upon incubation with 11b-HSD1 inhibitor, indicating the existence of another carbonyl reductase that generates erythrohydrobupropion. Molecular docking supported the experimental findings and suggested that 11b-HSD1 selectively converts R-bupropion to threohydrobupropion. Enzyme inhibition experiments suggested that exposure to bupropion is not likely to impair 11b-HSD1-dependent glucocorticoid activation but that pharmacological administration of cortisone or prednisone may inhibit 11b-HSD1-dependent bupropion metabolism.

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Section: Discussionmentioning

confidence: 99%

Formation of Threohydrobupropion from Bupropion Is Dependent on 11β-Hydroxysteroid Dehydrogenase 1

et al. 2013

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“…This reaction has frequently been used to assess the effect of genetic and nongenetic factors influencing CYP2B6 activity in vitro and in vivo. However, the significant contribution of non-cytochrome P450-mediated pathways, the involvement of cytochrome P450 enzymes other than CYP2B6 in overall BUP metabolism, the elimination rate-limited kinetics of OHBUP, and the complex pharmacokinetics of BUP and its metabolites may limit the utility of racemic BUP as a quantitative in vivo probe of CYP2B6 activity (Palovaara et al, 2003;Turpeinen et al, 2005;Loboz et al, 2006;Kharasch et al, 2008;Ilic et al, 2013). This assertion is particularly important in assessment of DDIs mediated via induction (Xu et al, 2007) and functional consequences of genetic variants (Kirchheiner et al, 2003).…”

Section: Chiral Pharmacokinetics Of Bupropion and Metabolitesmentioning

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

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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.

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“…Palovaara et al 43 reported that hormone replacement therapy (HRT) markedly inhibited the CYP2B6-catalyzed hydroxylation of bupropion, whereas a combination oral contraceptive had only a modest effect on CYP2B6 activity, suggesting that patients receiving HRT or oral contraceptives may need dose adjustment when treated with drugs metabolized by CYP2B6. Variations in estrogen level and their impact on CYP2B6 activity could explain women's variable response to bupropion in this trial.…”

Section: Ge Swan Et Almentioning

confidence: 99%

Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR

et al. 2004

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The A1 allele of the dopamine D2 receptor gene (DRD2) is associated with a reduced number of dopamine binding sites in the brain and with the increased likelihood of substance abuse and addictive behavior. In a study of smokers enrolled in an open-label, randomized effectiveness trial, we investigated whether variants in the DRD2 receptor gene are associated with smoking cessation outcomes following treatment with a combination of bupropion SR and behavioral counseling. Adherence to treatment and pointprevalent smoking status were assessed at 3 and 12 months, respectively, following a target quit date. Compared to women who carry both A2 alleles, women with at least one A1 allele were more likely to report having stopped taking bupropion due to medication side effects (odds ratio (OR) ¼ 1.91, 95% confidence interval (CI) ¼ 1.01-3.60; Po0.04) and at 12 months were somewhat more likely to report smoking (OR ¼ 0.76, 95% CI ¼ 0.56-1.03; Po0.076). Significant associations or trends were not observed in men. In women, individual variability in responsiveness to bupropion-based treatment may be partially due to differences in genetic variants influencing dopamine receptor function. INTRODUCTIONTobacco use remains the major preventable cause of premature disability and death in developed countries. Despite best efforts to date, 46 million people still smoke in the United States, and over 440 000 people die each year from tobaccorelated illness; the estimated smoking-related cost to the economy is $157 billion annually.1 Effective pharmacologic interventions for smoking cessation include several forms of nicotine replacement and the use of the antidepressant medication, bupropion.2 Despite treatment advances, smoking relapse after successful intervention for smoking cessation occurs in 70 to 80% of patients within 12 months. [3][4][5] Still to be determined is why some people remain nonsmokers after pharmacologic intervention and others do not.The dopaminergic mesocorticolimbic pathway in the brain is thought to play an important role in tobacco and nicotine addiction. [6][7][8] The TaqIA polymorphism of the dopamine D2 receptor gene (DRD2) results from a C/T

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Inhibition of cytochrome P450 2B6 activity by hormone replacement therapy and oral contraceptive as measured by bupropion hydroxylation

Cited by 76 publications

References 29 publications

Formation of Threohydrobupropion from Bupropion Is Dependent on 11β-Hydroxysteroid Dehydrogenase 1

Formation of Threohydrobupropion from Bupropion Is Dependent on 11β-Hydroxysteroid Dehydrogenase 1

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

Dopamine receptor DRD2 genotype and smoking cessation outcome following treatment with bupropion SR

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