BIDIRECTIONAL CHIRAL INVERSION OF THE ENANTIOMERS OF THE NONSTEROIDALANTIINFLAMMATORY DRUG OXINDANAC IN DOGS

The nonsteroidal antiinflammatory drug oxindanac exists as two enantio mers, with most of its pharmacological activity residing in the (S)-is omer. The behavior of its enantiomers was investigated in dogs. Bidire ctional inversion occurred in heparinised plasma and blood, with a rat io of enantiomers [S:R] of 7.3:1 being achieved at equilibrium after i ncubation for 24 h at 37 degrees C. There was no detectable inversion of either isomer in plasma incubated at 4 degrees C for up to 8 h or i n aqueous solution at 37 degrees C for up to 36 h. Bidirectional inver sion also occurred in vivo, with a ratio of plasma AUC (O infinity)s [ S:R] of 8.1:1. The ratio of enantiomers reached equilibrium within 2 h r following (S)- or rac-oxindanac, and within 8 h following (R)-oxinda nac. Elimination t1/2s of the isomers were the same (R, 12.1 h, S, 13. 3 h). There were no differences in the ratio of enantiomers following oral or intravenous application, suggesting that a systemic site for i nversion was predominant. Although concentrations of the respective is omers were similar at equilibrium following administration of either ( R)-, (S)-, or rac-oxindanac, AUC (O infinity)S differed due to the del ay in reaching equilibrium. The extent of inversion to the (S)-isomer was 100, 73.2, and 60.7% after administration of(S)-, rac-, and (R)-ox indanac, respectively. Although pharmacological activity might be equi valent at equilibrium following administration of either (R)-, (S)-, o r rac-oxindanac; efficacy at early time points should be superior in t he order (S) > racemate > (R). In conclusion both enantiomers of oxind anac undergo conversion to their respective antipodes in dogs, althoug h the inversion of R to S is more efficient than that of S to R. This bidirectional inversion occurred in vivo, and in vitro in plasma and b lood. (C) 1994 Wiley-Liss, Inc.