Stereoselective disposition of ibuprofen and flurbiprofen in rats

(R)‐2‐Arylpropionates are often inverted to the pharmacologically active S‐enantiomers in vivo, although there is significant interspecies variability in inversion. In order to provide a basis for determining the biochemical consequences of this unique process using rats as a model, it was important to establish the pharmacokinetic disposition of the enantiomers of ibuprofen, a drug well inverted in man and flurbiprofen, a drug apparently poorly inverted in man. Rats were dosed i.v. with a single dose of (R)‐or (S)‐ibuprofen (20 mg/kg), (R,S)‐ibuprofen (40 mg/kg), (R)‐ or (S)‐flurbiprofen (10 mg/kg), or (R,S)‐flurbiprofen (20 mg/kg). Each treatment group consisted of six animals. Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen. These drugs were assayed in plasma by a stereospecific HPLC assay. The pharmacokinetics of the ibuprofen and flurbiprofen enantiomers were evaluated using a two‐compartment open model with conversion of the R‐ to S‐enantiomers in the central compartment. There was 50 ± 4% inversion of (R)‐ibuprofen, a figure similar to that observed in man and (R)‐ibuprofen had a higher clearance (12.6 ± 1.3 ml/min/kg) than (S)‐ibuprofen (7.7 ± 0.7 ml/min/kg; P < 0.01). The clearance of (R)‐ flurbiprofen after racemate (2.3 ± 0.1 ml/min/kg) was higher than its clearance when administered alone (1.7 ± 0.2 ml/min/kg; P < 0.01), indicating a pharmacokinetic interaction between the enantiomers (most probably at plasma protein binding sites). A corresponding difference was not observed for ibuprofen. There was a small amount of inversion of (R)‐flurbiprofen as determined by area analysis (4.5 ± 1.6%). However, this calculation may be in some error because of the interaction between the enantiomers. These data demonstrate quantitative similarities in the inversion of ibuprofen and flurbiprofen in rats and man, a useful basis for comparing the effects of these two drugs on fatty acid metabolism.