Oxindanac

The pharmacokinetics and pharmacodynamics of the non‐steroidal antiinflammatory drug, oxindanac, were assessed simultaneously in calves after intravenous (i.v.) administration at dose rates of 0.5, 1, 2, 4 and 8 mg/kg. Plasma pharmacokinetic data were fitted to either two or three compartment open models. The eliminationt1/2was constant in the dose range 0.5 to 4 mg/kg (20.2–22.8 h) and shorter at 8 mg/kg (14.7 h). The pharmacodynamics of oxindanac were assessed by its inhibition of serum TxB2, an index of platelet cyclo‐oxygenase activity. Plots of total plasma oxindanac concentration vs. inhibition of serum TxB2fitted in all cases a sigmoidal Emaxequation. There were no significant differences in the estimates for ED50(1.6‐1.9 μg/ml), Hill constant (1.3‐2.7) or Emax between the doses used in thein vivostudies or when blood was spiked with oxindanacin vitro.Plots of inhibition of serum TxB2vs. time were prepared from the pharmacokinetic model equations in each calf in combination with a single sigmoidal Emaxplot generatedin vitro.These data were not significantly different from the results producedin vivo.It is concluded that oxindanac causes reversible inhibition of platelet cyclo‐oxygenase in calves. Its inhibition of serum TxB2can be predicted from total plasma drug concentration, as described by a multicompartmental model, and sigmoidal Emaxenzyme kinetics. It was not necessary to take into account factors such as drug equilibration between plasma and its target site, free vs. total drug concentration or chirality. This simple model may be useful for predicting the pharmacodynamics of oxindanac in other species.

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°C. There was no detectable inversion of either isomer in plasma incubated at 4°C for up to 8 h or in aqueous solution at 37°C for up to 36 h. Bidirectional inversion also occurred in vivo, with a ratio of plasma AUC (0 ∞)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 t½s 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 ∞)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). In conclusion both enantiomers of oxindanac undergo conversion to their respective antipodes in dogs, although 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 blood. © 1994 Wiley‐Liss, Inc.