Human CYP2B6: Induction by ethanol and polymorphisms

Tufts University Boston, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Alcohol is consumed worldwide in tremendous amounts. Depending on exposure duration, alcohol induces or inhibits drug metabolism. Human liver microsomes from donors reported to have consumed at least 14 alcoholic beverages per week have high CYP2B6 activity (bupropion hydroxylation) per milligram of microsomal protein in vitro. Furthermore, high CYP2B6 activity correlates significantly with the absence of a CYP2B6*6B allele. The aims of this research are to test the hypotheses that 1) alcohol induces bupropion hydroxylation (CYP2B6 probe), and 2) the presence of at least one CYP2B6*6B allele restricts this inductive effect, supporting in vitro results. The pharmacokinetics of bupropion and hydroxybupropion will be assessed in a three-group clinical study involving healthy volunteers who typically drink or abstain from alcohol. Pharmacokinetics will be compared in drinkers with at least one CYP2B6*6B allele versus drinkers with no CYP2B6*6B allele. Results will provide clinical data on the inducibility of CYP2B6 by alcohol. Results may indicate that genotyping patients is advantageous before prescribing a CYP2B6 substrate to perhaps avoid adverse events such as seizures (bupropion) or inefficient HIV therapy (efavirenz).