Ketoprofen (KT; m-benzoylhydratropic acid), a 2-arylpropionic acid (2-APA) nonsteroidal anti-inflammatory drug (NSAID), is marketed and used as a racemic mixture. Although generally the activity of 2-APAs is suggested to be mainly due to the S-enantiomer, information on KT pharmacokinetics is based on measurement of total concentrations of S- and R-enantiomers. In this work, using a crossover fashion, the pharmacokinetics of KT enantiomers following single (50 mg, po) and then multiple (50 mg, q6h for 3 d) doses were delineated in eight healthy subjects. A sensitive stereospecific HPLC assay was used to measure KT enantiomers in plasma and urine, and conjugated KT enantiomers in urine. There were no significant differences between the pharmacokinetic indices calculated after single and multiple administration of KT. In plasma, small but significant differences were found between concentrations of the enantiomers (mean S:R ratios of 0.81 +/- 0.19 after single and 0.87 +/- 0.11 after repeated doses). Negligible amounts of unchanged KT enantiomers were found in urine. More than 80% of the given doses was found in urine as conjugated S- and R-KT, the predominant enantiomer being S-KT (mean S:R ratios of 1.19 +/- 0.05 after single and 1.17 +/- 0.05 after repeated doses). No significant difference between the elimination t1/2 of the enantiomers was observed. It is suggested that stereoselective conjugation followed by preferential biliary excretion of the conjugated R-KT enantiomer is responsible for the observed stereoselectivity in the pharmacokinetics of the drug.