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Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition
Author(s) -
Kharasch Evan D.,
Crafford Amanda
Publication year - 2019
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.1116
Subject(s) - bupropion , cyp2b6 , pharmacology , cyp2c19 , chemistry , cyp3a4 , hydroxylation , cytochrome p450 , medicine , metabolism , biochemistry , smoking cessation , enzyme , pathology
Bupropion hydroxylation is a bioactivation and metabolic pathway, and the standard clinical CYP2B6 probe. This investigation determined the influence of CYP2B6 allelic variants on clinical concentrations and metabolism of bupropion enantiomers. Secondary objectives evaluated the influence of CYP2C19 and P450 oxidoreductase variants. Healthy volunteers in specific cohorts ( CYP2B6*1/*1, CYP2B6*1/*6, CYP2B6*6/*6 , and also CYP2B6*4 carriers) received single‐dose oral bupropion. Plasma and urine bupropion and hydroxybupropion was quantified. Subjects were also genotyped for CYP2C19 and P450 oxidoreductase variants. Hydroxylation of both bupropion enantiomers, assessed by plasma hydroxybupropion/bupropion AUC ratios and urine hydroxybupropion formation clearances, was lower in CYP2B6*6/*6 but not CYP2B6*1/*6 compared with CYP2B6*1/*1 genotypes, and numerically greater in CYP2B6*4 carriers. CYP2C19 and P450 oxidoreductase variants did not influence bupropion enantiomers hydroxylation or plasma concentrations. The results show that clinical hydroxylation of both bupropion enantiomers was equivalently influenced by CYP2B6 allelic variation. CYP2B6 polymorphisms affect S‐bupropion bioactivation, which may affect therapeutic outcomes.