Pharmacokinetic Optimisation of Sustained-Release Bupropion for Smoking Cessation

Johnston, J. Andrew; Ascher, John; Leadbetter, Robert A.; Schmith, Virginia D.; Patel, Disha; Durcan, Michael J.; Bentley, Beth

doi:10.2165/00003495-200262002-00002

Cited by 77 publications

(84 citation statements)

References 32 publications

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“…The increased hydroxylation of bupropion with significant reduction in bupropion plasma concentration by metamizole seen in our study may reduce the clinical effects by bupropion since the pharmacological activity of hydroxybupropion is about half that of bupropion [16]. Still, it is uncertain to what degree the efficacy of bupropion may be influenced by metamizole due to the pharmacodynamic variability of bupropion [17,18].…”

Section: Discussionmentioning

confidence: 70%

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Qin

Zhang

Liu

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Bupropion, an antidepressant and smoking cessation drug, is metabolized to its active metabolite, 4-hydroxybupropion, almost exclusively by CYP2B6.• Metamizole, a pyrazolone derivative with analgesic properties, was shown in an in vitro study to increase significantly the expression of CYP2B6 and bupropion hydroxylase activity.• The effect of metamizole on bupropion hydroxylation has not been investigated and drug interactions may occur between metamizole and bupropion. WHAT THIS PAPER ADDS• Oral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects.• Dosage adjustment of bupropion may be needed in patients when metamizole is concomitantly administered. AIMSThis study aimed to investigate the effect of metamizole on bupropion hydroxylation related to different CYP2B6 genotype groups in healthy volunteers. METHODSSixteen healthy male volunteers (6 CYP2B6*1/*1, 6 CYP2B6*1/*6 and 4 CYP2B6*6/*6) received orally administered bupropion alone and during daily treatment with metamizole 1500 mg day -1 (500 mg tablet taken three times daily) for 4 days. Serial blood samples were obtained up to 48 h after each bupropion dose. RESULTSAfter metamizole treatment relative to bupropion alone, the geometric mean ratios (GMRs) and 90% confidence interval (CI) of the AUC(0,•) ratio of 4-hydroxybupropion over bupropion were 1.99 (1.57, 2.55) for the CYP2B6*1/*1 group, 2.15 (1.53, 3.05) for the CYP2B6*1/*6 group and 1.86 (1.36, 2.57) for the CYP2B6*6/*6 group. The GMRs and 90% CI of bupropion were 0.695 (0.622, 0.774) for AUC(0,•) and 0.400 (0.353, 0.449) for Cmax, respectively. The corresponding values for 4-hydroxybupropion were 1.43 (1.28, 1.53) and 2.63 (2.07, 2.92). The t1/2 value was significantly increased for bupropion and decreased for 4-hydroxybupropion. The tmax values of bupropion and 4-hydroxybupropion were both significantly decreased. The mean percentage changes in pharmacokinetic parameters among the CYP2B6 genotype groups were not significantly different. CONCLUSIONSOral administration of metamizole for 4 days significantly altered the pharmacokinetics of both bupropion and its active metabolite, 4-hydroxybupropion, and significantly increased the CYP2B6-catalyzed bupropion hydroxylation in all of the subjects. Cautions should be taken when metamizole is co-administered with CYP2B6 substrate drugs.

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Section: Discussionmentioning

confidence: 70%

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Qin

Zhang

Liu

et al. 2012

Brit J Clinical Pharma

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“…These effects return to baseline within several hours (5,10,15). Peak plasma values are reached within three hours of ingestion, the mean elimination half-life is 21 hours, and bupropion is extensively metabolised by multiple pathways, with no single pathway predominating (16).…”

Section: Discussionmentioning

confidence: 99%

Cardiogenic shock and status epilepticus after massive bupropion overdose

Morazin

Lumbroso

Harry

et al. 2007

Clinical Toxicology

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Background. To describe a profound cardiac dysfunction and a status epilepticus after a massive bupropion overdose. Case report. A 35-year-old man was admitted in coma following the deliberate ingestion of 12 g of bupropion. The course was marked by the rapid onset of severe and prolonged status epilepticus and cardiogenic shock. Plasma bupropion level determined four hours after the estimated time of ingestion was 1.4 mg/L. All clinical features resolved completely in response to symptomatic treatment. Conclusion. Several cases of bupropion overdose, with sinus tachycardia and seizures rapidly corrected by symptomatic treatment, have been reported in the literature. To our knowledge, this case of overdose with bupropion alone, at very high doses, is the first to describe clinical features comprising severe and prolonged status epilepticus and direct cardiotoxicity with the development of cardiogenic shock documented by echocardiogram.

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“…The quantitative aspects were estimated using the study published by Benowitz et al (2013). The metabolic pathway data were compiled from Butz et al (1981), , DeVane et al (1990), Sweet et al (1995), Hsyu et al (1997), Faucette et al (2000), (Johnston et al (2002), Chen et al (2010), and Meyer et al (2013). More than 20 bupropion metabolites have been identified; some poorly characterized secondary and tertiary metabolites are not shown on this figure.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Pharmacokinetic Optimisation of Sustained-Release Bupropion for Smoking Cessation

Cited by 77 publications

References 32 publications

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Rapid clinical induction of bupropion hydroxylation by metamizole in healthy Chinese men

Cardiogenic shock and status epilepticus after massive bupropion overdose

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

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