Effect of non-linear plasma protein binding on unbound and total plasma phenylbutazone concentrations in cows

The influence of plasma protein binding on unbound and total phenylbutazone concentrations in cows was examined employing data from the literature. Protein binding parameters (number of binding sites and affinity constants) were generated by computer analysis to characterize the concentration-dependent plasma protein binding of phenylbutazone. Unbound plasma phenylbutazone concentrations were calculated from total plasma drug concentrations observed after administration of a single dose of phenylbutazone to cows. Pharmacokinetic parameters for unbound phenylbutazone were obtained. Parameters characterizing the plasma protein binding and pharmacokinetics of unbound phenylbutazone derived from single-dose administration were then used to predict unbound and total drug concentrations after multiple-dose administration of phenylbutazone. Total plasma phenylbutazone concentrations predicted from single-dose pharmacokinetic parameters agreed well with observed values following multiple-dose administration of the drug. Thus, the results of this analysis demonstrate that the non-linear pharmacokinetics of phenylbutazone in the cow can be attributed to the concentration-dependent plasma protein binding of the drug.