INFLUENCE OF THE ROUTE OF ADMINISTRATION ON THE PHARMACOKINETICS OF PIRPROFEN ENANTIOMERS IN THE RAT

The pharmacokinetics of the enantiomers of the non-steroidal anti-inflammatory drug pirprofen were studied in male Sprague-Dawley rats after oral and intravenous (iv) doses of the racemate. No significant differences were detected between the enantiomers after oral or iv dosing in t1/2, Vd, or SIGMAXu. However, the R:S area under the plasma concentration (AUC) ratio after oral doses (0.92 +/- 0.13) was slightly but significantly lower than after matching iv doses (1.05 +/- 0.036). The absolute bioavailability of the active S-enantiomer (78.5%) after oral doses was higher than the inactive R-enantiomer (69.3%). The plasma protein binding of both enantiomers was saturable over a fivefold range of plasma concentrations. At higher plasma concentrations, the S-enantiomer was less bound than the R-enantiomer. In an in vitro experiment using everted rat jejunum, no chiral inversion was discernible. The dependency of the AUC ratio of the enantiomers on the route of administration may be due to stereoselective first-pass metabolism.