Marion Bessin Liver Research Center, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
Division of Gastroenterology and Liver Diseases, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA.
Clin Pharmacol Drug Dev. 2017 Mar;6(2):140-146. doi: 10.1002/cpdd.314.
Hyperbilirubinemia is a common finding in individuals with a history of substance abuse. Although this may indicate a serious disorder of liver function, this is not always the case. An understanding of bilirubin formation, metabolism, and transport can provide a helpful approach to dealing with these patients. This is typified by studies of patients treated with the antiretroviral drug atazanavir. Atazanavir has been associated with hyperbilirubinemia in as many as one-third of individuals for whom it has been prescribed, evoking concerns of hepatotoxicity. The studies in this report were designed to determine mechanisms by which this occurs. The data show that this drug inhibits the enzyme UDP-glucuronosyl transferase-1A1, responsible for conjugating bilirubin with glucuronic acid. This conjugation step is required for bilirubin excretion into bile, and when it is inhibited, bilirubin refluxes from the liver into the circulation, causing unconjugated hyperbilirubinemia. Other parameters of bilirubin formation, binding to albumin in the circulation, uptake into hepatocytes, and intracellular protein binding in hepatocytes were unaffected by atazanavir. The effect of atazanavir on serum bilirubin levels is reversible, consistent with lack of structural damage to the liver.
高胆红素血症是有药物滥用史个体的常见表现。尽管这可能表明肝脏功能严重紊乱，但情况并非总是如此。了解胆红素的形成、代谢和转运有助于为这些患者提供帮助。这可以通过对接受抗逆转录病毒药物阿扎那韦治疗的患者的研究来说明。阿扎那韦在多达三分之一的处方患者中引起高胆红素血症，引起了肝毒性的担忧。本报告中的研究旨在确定发生这种情况的机制。数据表明，这种药物抑制了 UDP-葡糖醛酸基转移酶-1A1 的酶，该酶负责将胆红素与葡糖醛酸结合。这个结合步骤是将胆红素排入胆汁所必需的，当它被抑制时，胆红素从肝脏反流到循环中，导致未结合的高胆红素血症。胆红素形成的其他参数，如在循环中与白蛋白结合、被肝细胞摄取以及在肝细胞内的蛋白质结合，不受阿扎那韦的影响。阿扎那韦对血清胆红素水平的影响是可逆的，与肝脏结构损伤无关。
