KETOPROFEN PROBENECID INTERACTION IN THE RAT - A PROBENECID CONCENTRATION-DEPENDENT STEREOSELECTIVE PROCESS

Probenecid (PB) is believed to interact with the chiral nonsteroidal anti-inflammatory drug ketoprofen (KT) through competition for glucuronide conjugation and subsequent renal and/or biliary excretion of formed KT conjugates. It is unknown whether the interaction is dependent on PB concentration and whether both KT enantiomers are affected to the same extent. We measured intact and conjugated R-KT, S-KT, and PB in the plasma and urine of female Sprague-Dawley rats after intravenous doses of 10 mg of racemic KT per kg and 0, 25, 50, 100, 150, 175, and 200 mg of PB per kg. Elevated levels of both enantiomers were observed, with S-KT being affected to a much greater extent. Significant positive correlations were found between the concentrations in plasma of KT enantiomers and PB at various sampling times, with the strongest correlations being found at 2 h for R-KT (r = 0.708) and 1.5 h for S-KT (r = 0.913). The areas under the concentration-time curve (AUC) from 0-24 h for R-KT (r = 0.697) and S-KT (r = 0.848) also showed strong correlation with AUC of PB. Our data show that as the dose of PB was increased (0-200 mg/kg), the mean S-KT/R-KT ratios for both the AUC and the fraction of the dose excreted as enantiomer conjugates in urine over 24 h increased progressively from 12.1 +/- 2.3 to 27.6 +/- 5.0 and from 6.8 +/- 0.7 to 36.4 +/- 12.2, respectively. These findings clearly demonstrate that the KT-PB interaction in the rat is a PB concentration-dependent process. The importance of considering stereochemistry in evaluating potential drug interactions is also highlighted.