Stereoselective analysis of hydroxybupropion and application to drug interaction studies

Chirality. 2007 Mar;19(3):163-70. doi: 10.1002/chir.20356.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Antibiotics, Antitubercular / pharmacokinetics
  • Antidepressive Agents, Second-Generation / analysis*
  • Antidepressive Agents, Second-Generation / chemistry*
  • Antidepressive Agents, Second-Generation / isolation & purification
  • Antidepressive Agents, Second-Generation / pharmacokinetics
  • Bupropion / analogs & derivatives*
  • Bupropion / analysis
  • Bupropion / chemistry
  • Bupropion / isolation & purification
  • Bupropion / pharmacokinetics
  • Chromatography, High Pressure Liquid
  • Humans
  • Male
  • Rifampin / pharmacokinetics
  • Stereoisomerism

Substances

  • Antibiotics, Antitubercular
  • Antidepressive Agents, Second-Generation
  • Bupropion
  • radafaxine
  • Rifampin