Potent and highly selective inhibition of selpercatinib towards UDP-glucuronosyltransferase 1A4 (UGT1A4) isoform

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-05-10 DOI:10.1016/j.taap.2025.117393

Yueyi Liu , Xin Lv , Hang Yin , Lili Jiang

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Abstract

Selpercatinib is a potent and highly selective Rearranged during Transfection (RET) kinase inhibitor for patients with RET fusion-positive thyroid cancer and non-small-cell lung cancer. The present study aims to investigate the inhibitory effects of selpercatinib towards human UDP-glucuronosyltransferases (UGTs), and assess its risk for drug-drug interactions (DDIs) via UGT inhibition. The inhibition of selpercatinib towards 12 recombinant human UGT isoforms were measured. Our data demonstrated that selpercatinib exhibited highly selective inhibition towards UGT1A4. Enzyme kinetic study indicated that selpercatinib competitively inhibited the activity of UGT1A4, with a K_i value of 1.57 ± 0.14 μM. The quantitative prediction of DDIs risk indicated that the co-administration of selpercatinib with UGT1A4 substrate might trigger clinically significant DDIs. Additional caution should be taken to avoid unexpected DDIs when selpercatinib and other UGT1A4 substrates are combined.

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selpercatinib对udp -葡萄糖醛酸糖基转移酶1A4 （UGT1A4）亚型的有效和高选择性抑制

Selpercatinib是一种用于RET融合阳性甲状腺癌和非小细胞肺癌患者的强效和高选择性rearrangement during转染（RET）激酶抑制剂。本研究旨在探讨selpercatinib对人udp -葡萄糖醛酸糖基转移酶（UGT）的抑制作用，并通过UGT抑制评估其药物-药物相互作用（ddi）的风险。测定了selpercatinib对12种重组人UGT亚型的抑制作用。我们的数据表明，selpercatinib对UGT1A4具有高度选择性的抑制作用。酶动力学研究表明，selpercatinib竞争性抑制UGT1A4的活性，Ki值为1.57±0.14 μM。定量预测ddi风险表明，selpercatinib与UGT1A4底物合用可能引发临床显著性ddi。当selpercatinib和其他UGT1A4底物联合使用时，应注意避免意外的ddi。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.