Influence of CYP2B6 genetic variants on plasma and urine concentrations of bupropion and metabolites at steady state.
BACKGROUND
Bupropion, an antidepressant and smoking cessation medication, is metabolized to hydroxybupropion (HB), an active metabolite, primarily by CYP2B6.


OBJECTIVE
To compare plasma concentrations of bupropion and metabolites at steady state in healthy volunteers with and without CYP2B6 genetic variants.


METHODS
In a genotype-guided study of 42 healthy individuals, we measured the plasma and urine concentrations of bupropion and its metabolites, HB, threohydrobupropion, and erythrohydrobupropion after 7 days of sustained-release bupropion dosing.


RESULTS
CYP2B6*6 and *18 gene variants were associated with ~33% reduced concentrations of HB, with no effects on concentrations of bupropion or other metabolites. We could account for 50% of the variation in HB concentrations in a model including genotype and sex.


CONCLUSIONS
As HB is active and its steady-state concentrations are more than 10 times higher than bupropion, CYP2B6 variants are likely to affect pharmacological activity. Because of the large individual variation within the genotype group, the use of therapeutic drug monitoring for dose optimization may be necessary.
Department of Medicine, Bioengineering and Therapeutic Sciences, Division of Clinical Pharmacology and Experimental Therapeutics, University of California, San Francisco, California 94143-1220, USA. nbenowitz@medsfgh.ucsf.edu
Neal L
NL
Benowitz
Andy Z X
AZ
Zhu
Rachel F
RF
Tyndale
Delia
D
Dempsey
Peyton
P
Jacob
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001483:Base Sequence; D016642:Bupropion / Q000097:blood* / Q000652:urine*; D065702:Cytochrome P-450 CYP2B6; D017931:DNA Primers; D018765:Dopamine Uptake Inhibitors / Q000097:blood* / Q000652:urine*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D016133:Polymerase Chain Reaction
D017931:DNA Primers; D018765:Dopamine Uptake Inhibitors; D016642:Bupropion; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating