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Inhibition of Human UDP-Glucuronosyltransferase Enzyme by Belinostat: Implications for Drug-Drug Interactions
Toxicology Letters ( IF 2.9 ) Pub Date : 2021-03-01 , DOI: 10.1016/j.toxlet.2020.12.001
Xiaoyu Wang , Zhe Wang , Zhen Wang , Xiuyuan Chen , Hang Yin , Lili Jiang , Jun Cao , Yong Liu

Belinostat is a pan-histone deacetylase (HDAC) inhibitor which recently approved for the treatment of relapsed/refractory Peripheral T-cell lymphomas (PTCL). To assess drug-drug interactions (DDIs) potential of belinostat via inhibition of UDP-glucuronosyltransferases (UGTs), the effects of belinostat on UGTs activities were investigated using the non-selective probe substrate 4-methylumbelliferone (4-MU) and trifluoperazine (TFP) by UPLC-MS/MS. Belinostat exhibited a wide range of inhibition against UGTs activities, particularly a potent non-competitive inhibition against UGT1A3, and weak inhibition against UGT1A1, 1A7, 1A8, 2B4 and 2B7. Further, in vitro-in vivo extrapolation (IVIVE) approaches were used to predict the risk of DDI arising from inhibition of UGTs. Our data indicate that the intravenous infusion of belinostat at clinical available dose can contribute a significant increase to the AUC of co-administrated drugs primarily cleared by UGT1A3 or UGT1A1, which will result in potential DDIs. In contrast, oral administrated belinostat is unlikely to cause significant DDIs through inhibition of glucuronidation.

中文翻译:

贝利诺司他对人 UDP-葡萄糖醛酸转移酶的抑制作用:对药物-药物相互作用的影响

Belinostat 是一种泛组蛋白去乙酰化酶 (HDAC) 抑制剂,最近批准用于治疗复发/难治性外周 T 细胞淋巴瘤 (PTCL)。为了通过抑制 UDP-葡萄糖醛酸基转移酶 (UGT) 来评估贝立司他的药物-药物相互作用 (DDI) 潜力,使用非选择性探针底物 4-甲基伞形酮 (4-MU) 和三氟拉嗪 (TFP) 研究了贝立司他对 UGT 活性的影响) 通过 UPLC-MS/MS。Belinostat 表现出对 UGT 活性的广泛抑制,特别是对 UGT1A3 的有效非竞争性抑制,以及对 UGT1A1、1A7、1A8、2B4 和 2B7 的弱抑制。此外,体外-体内外推 (IVIVE) 方法用于预测因抑制 UGT 引起的 DDI 风险。我们的数据表明,以临床可用剂量静脉输注贝利司他可以显着增加主要由 UGT1A3 或 UGT1A1 清除的共同给药药物的 AUC,这将导致潜在的 DDI。相比之下,口服贝立司他不太可能通过抑制葡萄糖醛酸化而引起显着的 DDI。
更新日期:2021-03-01
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