title: Effect of heparin on bilirubin clearance in rats: pharmacokinetic consequences of extensive hepatic extraction of plasma protein binding inhibitors.
abstract: The purpose of this investigation was to determine the effect of heparin-induced endogenous inhibitors of plasma protein binding on the plasma concentrations of total (free plus bound) and free bilirubin in rats with experimental hyperbilirubinemia. Adult male rats received constant-rate intravenous infusions of bilirubin and, after attaining steady state, were given either an intravenous injection of heparin, 500 units/kg, or this injection plus a maintenance infusion of hepatin. Control animals received normal saline solution instead of heparin. The free fraction of bilirubin in plasma increased substantially within 2 min after heparin injection and remained elevated when heparin concentrations were sustained by infusion of the anticoagulant. Despite the decreased plasma protein binding of bilirubin, the plasma concentration of total bilirubin did not decrease (as it does, consistent with pharmacokinetic theory, following injection or infusion of certain other inhibitors of bilirubin binding) and the plasma concentration of free bilirubin did not return to normal (as observed previously after administration of other binding inhibitors) but remained elevated. These results are consistent with the recently demonstrated rapid and extensive hepatic extraction of heparin-induced endogenous inhibitors of plasma protein binding. The heparin interaction with bilirubin may be particularly serious because of the sustained elevation of free bilirubin concentrations in plasma and the potential neurotoxicity of free bilirubin.
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000097:blood / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D006493:Heparin / Q000494:pharmacology*; D006932:Hyperbilirubinemia / Q000139:chemically induced; D011485:Protein Binding / Q000187:drug effects*; D051381:Rats
chemical_list: D002352:Carrier Proteins; D006493:Heparin; D001663:Bilirubin