Stereoselective disposition of ibuprofen and flurbiprofen in rats

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Abstract
(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 Serial blood samples were withdrawn over a period of 6 h for ibuprofen and 10 h for flurbiprofen.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.