Stereoselective disposition of tiaprofenic acid enantiomers in rats

The pharmacokinetics and metabolic chiral inversion of the S(+)- and R(-)-enantiomers of tiaprofenic acid (S-TIA, R-TIA) were assessed in vivo in rats, and in addition the biochemistry of inversion was investigated in vitro in rat liver homogenates. Drug enantiomer concentrations in plasma were investigated following administration of S-TIA and R-TIA (i.p. 3 and 9 mg/kg) over 24 hr. Plasma concentrations of TIA enantiomers were determined by stereospecific HPLC analysis. After administration of R-TIA it was found that 1) there was a time delay of peak S-TIA plasma concentrations, 2) S-TIA concentrations exceeded R-TIA concentrations from approximately 2 hr after dosing, 3) Cmax and AUC(0-infinity) for S-TIA were greater than for R-TIA following administration of S-TIA, and 4) inversion was bidirectional but favored inversion of R-TIA to S-TIA. Bidirectional inversion was also observed when TIA enantiomers were incubated with liver homogenates up to 24 hr. However, the rate of inversion favored transformation of the R-enantiomer to the S-enantiomer. In conclusion, stereoselective pharmacokinetics of R- and S-TIA were observed in rats and bidirectional inversion in rat liver homogenates has been demonstrated for the first time. Chiral inversion of TIA may involve metabolic routes different from those associated with inversion of other 2-arylpropionic acids such as ibuprofen.