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)-ke toprofen [(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 bot h male and female monkeys. A high-performance liquid chromatographic ( HPLC) analysis was performed without derivatization of the samples, us ing a chiral column. The pharmacokinetic parameters for (S)-KP after a dministration 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; appar ent volume of distribution 0.74 +/- 0.24 and 1.16 +/- 0.76 liter/kg; m ean residence time 1.79 +/- 0.77 and 1.41 +/- 0.65 h; area under the c oncentration/time curve 14.16 +/- 2.93 and 7.31 +/- 2.98 mu g.h/ml. Fo rty-nine percent unidirectional bioinversion of (R)-KP to (S)-KP was o bserved in this species and the pharmacokinetic parameters for the (S) -KP resulting from this inversion were also calculated. In the study o f 6-month repeated administration of (S)-KP, linear pharmacokinetic be havior and no evidence of drug accumulation were observed at the three dose levels. (C) 1994 Wiley-Liss, Inc.