A model of thyroidectomized sheep intravenously supplemented with thyroid 
hormone (TH) was developed to mimic endogenous TH exposure and to analyze the 
impact on plasma TH homeostasis of xenobiotic interference with TH binding to 
plasma proteins. TH was displaced from plasma protein binding sites by using 
phenylbutazone (PBZ) as a test xenobiotic, to compare the effect of PBZ on 
steady state free and total plasma TH concentrations between the in vivo 
situation and an in vitro system. While PBZ increased free TH in vitro, PBZ 
administration in vivo produced an immediate reduction in both total and free 
plasma TH. The decrease in the total TH was consistent with a PBZ-induced 
displacement of TH from its plasma binding proteins, leading to an increase in 
total TH plasma clearance. However, this reduction in total TH was not expected 
to be accompanied by a parallel decrease in free plasma TH since the free TH is 
determined by the clearance of the free plasma TH. This suggested that PBZ may 
also have interfered with the clearance mechanisms of free TH. It can be 
concluded that our thyroidectomized sheep model enables a dual action of a 
xenobiotic on plasma TH to be distinguished, namely a displacement of TH from 
its binding proteins leading to a decrease in the total plasma concentration, 
which is not relevant to thyroid function versus an interference with the 
intrinsic TH clearance leading to a change in the free plasma TH, which has a 
major impact in terms of thyroid disruption.