Correlation between the pharmacokinetics of oxindanac and inhibition of serum thromboxane B2in calves

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Abstract
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.