title: Bidirectional chiral inversion of the enantiomers of the nonsteroidal antiinflammatory drug oxindanac in dogs.
abstract: The nonsteroidal antiinflammatory drug oxindanac exists as two enantiomers, with most of its pharmacological activity residing in the (S)-isomer. The behavior of its enantiomers was investigated in dogs. Bidirectional inversion occurred in heparinised plasma and blood, with a ratio of enantiomers [S:R] of 7.3:1 being achieved at equilibrium after incubation 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 in aqueous solution at 37 degrees C for up to 36 h. Bidirectional inversion also occurred in vivo, with a ratio of plasma AUC (0 infinity)s [S:R] of 8.1:1. The ratio of enantiomers reached equilibrium within 2 hr following (S)- or rac-oxindanac, and within 8 h following (R)-oxindanac. 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 inversion was predominant. Although concentrations of the respective isomers were similar at equilibrium following administration of either (R)-, (S)-, or rac-oxindanac, AUC (0 infinity)s differed due to the delay 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)-oxindanac, respectively. Although pharmacological activity might be equivalent at equilibrium following administration of either (R)-, (S)-, or rac-oxindanac; efficacy at early time points should be superior in the order (S) > racemate > (R).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: CIBA Animal Health, Centre de Recherches Agricoles, St. Aubin FR, Switzerland.
authors.forename: J N
authors.initials: JN
authors.lastname: King
authors.forename: C
authors.initials: C
authors.lastname: Mauron
authors.forename: C
authors.initials: C
authors.lastname: LeGoff
authors.forename: S
authors.initials: S
authors.lastname: Hauffe
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D004285:Dogs; D005260:Female; D007192:Indenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D013237:Stereoisomerism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007192:Indenes; C039724:oxindanac