Stereoselective disposition of tiaprofenic acid enantiomers in rats

The pharmacokinetics and metabolic chiral inversion of the S(+)- and R(-)-e nantiomers of tiaprofenic acid (S-TIA, R-TIA) were assessed in vivo in rats , and in addition the biochemistry of inversion was investigated in vitro i n rat liver homogenates. Drug enantiomer concentrations in plasma were inve stigated following administration of S-TIA and R-TIA (i.p. 3 and 9 mg/kg) o ver 24 hr. Plasma concentrations of TIA enantiomers were determined by ster eospecific HPLC analysis. After administration of R-TIA it was found that 1 ) there was a time delay of peak S-TLA plasma concentrations, 2) S-TIA conc entrations exceeded R-TIA concentrations from similar to 2 hr after dosing, 3) C-max and AUC((0-infinity)) for S-TIA were greater than for R-TIA follo wing administration of S-TIA and 4) inversion was bidirectional but favored inversion of R-TLA to S-TLA. Bidirectional inversion was also observed whe n TIA enantiomers were incubated with liver homogenates up to 24 hr. Howeve r, the rate of inversion favored transformation of the R-enantiomer to the S-enantiomer. In conclusion, stereoselective pharmacokinetics of R- and S-T LA were observed in rats and bidirectional inversion in rat liver homogenat es has been demonstrated for the first time. Chiral inversion of TIA may in volve metabolic routes different from those associated with inversion of ot her 2-arylpropionic acids such as ibuprofen. (C) 1999 Wiley-Liss, Inc.