Pharmacokinetics of ketoprofen enantiomers in monkeys following single and multiple oral administration.

Pharmacokinetic studies are reported after single oral administration of 3 mg/kg of stereochemically pure (S)-ketoprofen [(S)-KP] and (R)-ketoprofen [(R)-KP] to three male Cynomolgus monkeys and after repeated administration for 6 months of 3, 15 and 75 mg/kg/day of (S)-KP to both male and female monkeys. A high-performance liquid chromatographic (HPLC) analysis was performed without derivatization of the samples, using a chiral column. The pharmacokinetic parameters for (S)-KP after administration of (S)-KP and for (R)-KP after administration of (R)-KP were, respectively, elimination half-life 2.32 +/- 0.36 and 1.64 +/- 0.40 h; oral clearance 3.50 +/- 0.66 and 7.50 +/- 3.20 ml/min/kg; apparent volume of distribution 0.74 +/- 0.24 and 1.16 +/- 0.76 liter/kg; mean residence time 1.79 +/- 0.77 and 1.41 +/- 0.65 h; area under the concentration/time curve 14.16 +/- 2.93 and 7.31 +/- 2.98 micrograms.h/ml. Forty-nine percent unidirectional bioinversion of (R)-KP to (S)-KP was observed in this species and the pharmacokinetic parameters for the (S)-KP resulting from this inversion were also calculated. In the study of 6-month repeated administration of (S)-KP, linear pharmacokinetic behavior and no evidence of drug accumulation were observed at the three dose levels.