67589
document
Gene variants in CYP2C19 are associated with altered in vivo bupropion pharmacokinetics but not bupropion-assisted smoking cessation outcomes . 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 .
67590
Intervention_Pharmacological
bupropion
67591
Intervention_Pharmacological
Bupropion
67592
Intervention_Pharmacological
bupropion
67593
Intervention_Pharmacological
bupropion
67594
Intervention_Pharmacological
bupropion .
67595
Intervention_Pharmacological
bupropion
67596
Outcome_Physical
bupropion plasma levels .
67597
Outcome_Physical
mean bupropion AUC
67598
Outcome_Physical
higher threohydrobupropion
67599
Outcome_Physical
erythrohydrobupropion AUC
67600
Outcome_Physical
the hydroxybupropion/bupropion ratio
67601
Outcome_Physical
smoking cessation outcomes
67602
Outcome_Physical
hydroxybupropion
67603
Outcome_Physical
reduced CYP2C19 activity
67604
Outcome_Physical
the steady-state exposure to bupropion and its reductive metabolites threohydrobupropion and erythrohydrobupropion
67605
Outcome_Adverse-effects
the side effects and toxicity
67606
Participant_Condition
smoking cessation
67607
Participant_Sample-size
42
67608
Participant_Sample-size
540
67609
Participant_Condition
smokers
67610
Participant_Condition
smokers