Inhibition of human UDP-glucuronosyltransferase enzymes by lapatinib, pazopanib, regorafenib and sorafenib: Implications for hyperbilirubinemia

葡萄糖醛酸化 葡萄糖醛酸转移酶 拉帕蒂尼 药理学 瑞戈非尼 化学 微粒体 胆红素 索拉非尼 IC50型 生物化学 医学 肝细胞癌 内科学 体外 癌症 结直肠癌 曲妥珠单抗 乳腺癌
作者
John O. Miners,Nuy Chau,Andrew Rowland,Kushari Burns,Ross A. McKinnon,Peter I. Mackenzie,Geoffrey T. Tucker,Kathleen M. Knights,Ganessan Kichenadasse
出处
期刊:Biochemical Pharmacology [Elsevier BV]
卷期号:129: 85-95 被引量:63
标识
DOI:10.1016/j.bcp.2017.01.002
摘要

Kinase inhibitors (KIs) are a rapidly expanding class of drugs used primarily for the treatment of cancer. Data relating to the inhibition of UDP-glucuronosyltransferase (UGT) enzymes by KIs is sparse. However, lapatinib (LAP), pazopanib (PAZ), regorafenib (REG) and sorafenib (SOR) have been implicated in the development of hyperbilirubinemia in patients. This study aimed to characterise the role of UGT1A1 inhibition in hyperbilirubinemia and assess the broader potential of these drugs to perpetrate drug–drug interactions arising from UGT enzyme inhibition. Twelve recombinant human UGTs from subfamilies 1A and 2B were screened for inhibition by LAP, PAZ, REG and SOR. IC50 values for the inhibition of all UGT1A enzymes, except UGT1A3 and UGT1A4, by the four KIs were <10 μM. LAP, PAZ, REG and SOR inhibited UGT1A1-catalysed bilirubin glucuronidation with mean IC50 values ranging from 34 nM (REG) to 3734 nM (PAZ). Subsequent kinetic experiments confirmed that REG and SOR were very potent inhibitors of human liver microsomal β-estradiol glucuronidation, an established surrogate for bilirubin glucuronidation, with mean Ki values of 20 and 33 nM, respectively. Ki values for LAP and PAZ were approximately 1- and 2-orders of magnitude higher than those for REG and SOR. REG and SOR were equipotent inhibitors of human liver microsomal UGT1A9 (mean Ki 678 nM). REG and SOR are the most potent inhibitors of a human UGT enzyme identified to date. In vitro–in vivo extrapolation indicates that inhibition of UGT1A1 contributes significantly to the hyperbilirubinemia observed in patients treated with REG and SOR, but not with LAP and PAZ. Inhibition of other UGT1A1 substrates in vivo is likely.
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