Wiegand U W, Soda D M, Levy G
J Pharm Sci. 1980 Oct;69(10):1228-30. doi: 10.1002/jps.2600691032.
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.
本研究的目的是确定肝素诱导的血浆蛋白结合内源性抑制剂对实验性高胆红素血症大鼠血浆中总胆红素（游离胆红素与结合胆红素之和）和游离胆红素浓度的影响。成年雄性大鼠接受恒速静脉输注胆红素，在达到稳态后，分别静脉注射500单位/千克肝素，或该注射剂量加肝素维持输注。对照动物接受生理盐水而非肝素。肝素注射后2分钟内，血浆中胆红素的游离部分大幅增加，当通过输注抗凝剂维持肝素浓度时，该游离部分仍保持升高。尽管胆红素的血浆蛋白结合减少，但总胆红素的血浆浓度并未降低（如注射或输注某些其他胆红素结合抑制剂后，根据药代动力学理论会降低），游离胆红素的血浆浓度也未恢复正常（如先前给予其他结合抑制剂后所观察到的），而是保持升高。这些结果与最近证明的肝素诱导的血浆蛋白结合内源性抑制剂的快速和广泛肝脏摄取一致。由于血浆中游离胆红素浓度持续升高以及游离胆红素潜在的神经毒性，肝素与胆红素的相互作用可能特别严重。
