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Stereoselective analysis of hydroxybupropion and application to drug interaction studies
Author(s) -
Xu Hongmei,
Loboz Katarzyna K.,
Gross Annette S.,
McLachlan Andrew J.
Publication year - 2007
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20356
Subject(s) - chemistry , pharmacology , enantiomer , bupropion , stereoselectivity , pharmacokinetics , active metabolite , chromatography , stereochemistry , biochemistry , biology , medicine , pathology , smoking cessation , catalysis
A sensitive and stereoselective assay has been developed for the quantitation of the enantiomers of hydroxybupropion, an active metabolite of bupropion, in human plasma. The assay used liquid–liquid extraction and a Cyclobond I 2000 HPLC column with a mobile phase containing 3% acetonitrile, 0.5% triethylamine, and 20 mM ammonium acetate (pH 3.8). The technique was linear over the concentration range of 12.5–500 ng/ml for ( 2R,3R )‐ and ( 2S,3S )‐hydroxybupropion. The method was reproducible as both interday and intraday variabilities were less than 10% for both hydroxybupropion enantiomers. Overall extraction recovery of hydroxybupropion enantiomers and the internal standard phenacetin from plasma was greater than 80% and reproducible over the concentration range of 12.5–500 ng/ml for each enantiomer. The limit of quantification (LOQ) of hydroxybupropion enantiomers was 12.5 ng/ml. The stereoselective pharmacokinetics of both ( 2R,3R )‐ and ( 2S,3S )‐hydroxybupropion in healthy male subjects ( n = 16) were investigated after a single dose of ( rac )‐bupropion either alone or during rifampicin administration. ( 2R,3R )‐Hydroxybupropion was the predominant enantiomer present in plasma. A stereoselective effect of rifampicin on hydroxybupropion concentrations was observed, with rifampicin influencing the pharmacokinetics of each hydroxybupropion enantiomer in a different manner. The ratio of ( 2R,3R )‐hydroxybupropion (AUC 0–24 ) to ( 2S,3S )‐hydroxybupropion (AUC 0–24 ) increased from 4.9 ± 1.6 to 8.3 ± 1.9 during rifampicin administration ( P < 0.001). A time‐dependent change in the hydroxybupropion enantiomeric ratio was observed after ( rac )‐bupropion administration both before and during rifampicin coadministration, with an increase in the relative proportion of ( 2S,3S )‐hydroxybupropion over the 24 h postdose period. Chirality 19, 2007. © 2006 Wiley‐Liss, Inc.