title: Stereoselective analysis of hydroxybupropion and application to drug interaction studies.
abstract: 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.
authors.affiliation: Faculty of Pharmacy, University of Sydney, Australia.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Xu
authors.forename: Katarzyna K
authors.initials: KK
authors.lastname: Loboz
authors.forename: Annette S
authors.initials: AS
authors.lastname: Gross
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
mesh_terms: D000904:Antibiotics, Antitubercular / Q000493:pharmacokinetics; D018687:Antidepressive Agents, Second-Generation / Q000032:analysis* / Q000737:chemistry* / Q000302:isolation & purification / Q000493:pharmacokinetics; D016642:Bupropion / Q000031:analogs & derivatives* / Q000032:analysis / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D008297:Male; D012293:Rifampin / Q000493:pharmacokinetics; D013237:Stereoisomerism
chemical_list: D000904:Antibiotics, Antitubercular; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; C496215:radafaxine; D012293:Rifampin