Effect of Salicylic Acid on Pharmacokinetics of Free and Plasma Protein-Bound Bilirubin in Experimental Unconjugated Hyperbilirubinemia

Abstract

The effect of salicylic acid injection and infusion on the concentrations of free and total (sum of free and bound) unconjugated bilirubin in plasma was studied in hyperbilirubinémie rats. In vitro addition of salicylic acid, 5-30 mg/100 ml, to rat plasma containing bilirubin, 12.7 mg/100 ml, caused a pronounced, salicylate concentration-dependent increase in the free bilirubin concentration. Normal rats were made hyperbilirubinémie by continuous intravenous infusion of bilirubin; the concentrations of free and total unconjugated bilirubin in plasma, and of total unconjugated bilirubin in whole blood, were determined as a function of time. Rapid intravenous injection of salicylate caused a rapid and pronounced decrease of total bilirubin concentrations in plasma and whole blood but had no apparent effect on the concentration of free bilirubin in plasma. Similar effects were obtained with slow infusions of salicylate, except that total bilirubin concentrations decreased gradually. These observations are consistent with the theory that the clearance rate of bilirubin by the body is proportional to the concentration of free bilirubin in plasma and that the steady-state concentration of free bilirubin depends only on the formation rate and intrinsic clearance of the pigment and is not affected by displacement of bilirubin from plasma protein binding sites. Occasional cases of acute apparent bilirubin intoxication were associated with unusually elevated concentrations of free bilirubin, reflecting a decreased intrinsic metabolic clearance of the pigment.