Common Polymorphisms of CYP2B6 Influence Stereoselective Bupropion Disposition

Clinical Pharmacology and Therapeutics
Evan D Kharasch, Amanda Crafford

Abstract

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.

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Citations

May 28, 2019·Drug Metabolism Reviews·Rafaela CostaRicardo Jorge Dinis-Oliveira
Apr 3, 2020·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Pan-Fen WangEvan D Kharasch
May 10, 2020·Clinical Pharmacology and Therapeutics·Evan D KharaschEric J Lenze
Dec 17, 2020·Expert Opinion on Drug Metabolism & Toxicology·Yadira X Perez-Paramo, Philip Lazarus
Nov 4, 2021·Expert Opinion on Drug Metabolism & Toxicology·Denise TürkThorsten Lehr

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