Pharmacokinetics of ketoprofen enantiomers in cholecystectomy patients: influence of probenecid

Abstract

Ketoprofen (KT), a 2-arylpropionic acid nonsteroidal antiinflammatory drug, is administered as a racemate. Previous reports suggest stereoselective biliary excretion of KT enantiomers. This hypothesis was tested by administering 50 mg racemic KT to five patients who required bile drainage following cholecystectomy surgery. Subsequently, to study the influence of probenecid (PB), an inhibitor of KT renal elimination, on the biliary excretion, 1000 mg PB was administered 1.5 h before KT to the same patients. The unchanged and conjugated (as glucuronides) KT enantiomers were measured in plasma, urine and bile. In general, KT enantiomers had different plasma concentration-time curves. As compared to normal subjects, these patients had comparable AUCs and shorter t1/2s. Biliary concentrations of conjugated S-KT were greater than R-KT. Nevertheless, the total cumulative biliary excretion of conjugated KT did not exceed 2% of the dose ruling out this pathway as a significant route of KT elimination. There was a positive and significant correlation between the cumulative urinary excretion of conjugated KT enantiomers and creatinine clearance. Although PB did not influence the pattern of stereoselectivity of KT, it increased AUC and prolonged t1/2 of the enantiomers. While reducing cumulative urinary excretion, PB increased total biliary elimination of conjugated KT enantiomers. This, however, did not totally compensate for the reduced urinary excretion. It is suggested that the impaired conjugation of KT caused by PB administration may result in the augmentation of other, otherwise minor, metabolic pathways.