Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by darolutamide: Prediction of in vivo drug-drug interactions

IF 4.7 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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Abstract

Darolutamide is a potent second-generation, selective nonsteroidal androgen receptor inhibitor (ARI), which has been approved by the US Food and Drug Administration (FDA) in treating castrate-resistant, non-metastatic prostate cancer (nmCRPC). Whether darolutamide affects the activity of UDP-glucuronosyltransferases (UGTs) is unknown. The purpose of the present study is to evaluate the inhibitory effect of darolutamide on recombinant human UGTs and pooled human liver microsomes (HLMs), and explore the potential for drug-drug interactions (DDIs) mediated by darolutamide through UGTs inhibition. The product formation rate of UGTs substrates with or without darolutamide was determined by HPLC or UPLC-MS/MS to estimate the inhibitory effect and inhibition modes of darolutamide on UGTs were evaluated by using the inhibition kinetics experiments. The results showed that 100 μM darolutamide exhibited inhibitory effects on most of the 12 UGTs tested. Inhibition kinetic studies of the enzyme revealed that darolutamide noncompetitively inhibited UGT1A1 and competitively inhibited UGT1A7 and 2B15, with the Ki of 14.75 ± 0.78 μM, 14.05 ± 0.42 μM, and 6.60 ± 0.08 μM, respectively. In particular, it also potently inhibited SN-38, the active metabolite of irinotecan, glucuronidation in HLMs with an IC50 value of 3.84 ± 0.46 μM. In addition, the in vitro-in vivo extrapolation (IVIVE) method was used to quantitatively predict the risk of darolutamide-mediated DDI via inhibiting UGTs. The prediction results showed that darolutamide may increase the risk of DDIs when administered in combination with substrates of UGT1A1, UGT1A7, or UGT2B15. Therefore, the combined administration of darolutamide and drugs metabolized by the above UGTs should be used with caution to avoid the occurrence of potential DDIs.

Abstract Image

达罗鲁胺对人类 UDP-葡萄糖醛酸转移酶(UGT)的抑制:体内药物相互作用的预测
达罗鲁胺是一种强效的第二代选择性非甾体雄激素受体抑制剂(ARI),已被美国食品药品管理局(FDA)批准用于治疗对阉割有抵抗力的非转移性前列腺癌(nmCRPC)。达罗鲁胺是否会影响UDP-葡萄糖醛酸转移酶(UGTs)的活性尚不清楚。本研究旨在评估达罗鲁胺对重组人UGTs和集合人肝微粒体(HLMs)的抑制作用,并探讨达罗鲁胺通过抑制UGTs介导的药物间相互作用(DDIs)的可能性。通过HPLC或UPLC-MS/MS测定UGTs底物在有达罗鲁胺或无达罗鲁胺情况下的产物形成率,以估算达罗鲁胺对UGTs的抑制作用,并利用抑制动力学实验评估达罗鲁胺对UGTs的抑制模式。结果表明,100 μM 达罗鲁胺对所测试的 12 种 UGTs 中的大多数具有抑制作用。酶抑制动力学研究显示,达罗鲁胺对 UGT1A1 具有非竞争性抑制作用,对 UGT1A7 和 2B15 具有竞争性抑制作用,Ki 分别为 14.75 ± 0.78 μM、14.05 ± 0.42 μM 和 6.60 ± 0.08 μM。特别是,它还能有效抑制伊立替康的活性代谢产物 SN-38在 HLMs 中的葡萄糖醛酸化,IC50 值为 3.84 ± 0.46 μM。此外,还采用体外-体内外推法(IVIVE)定量预测了达罗洛胺通过抑制 UGTs 介导的 DDI 风险。预测结果显示,当达罗鲁胺与 UGT1A1、UGT1A7 或 UGT2B15 的底物联合用药时,可能会增加 DDI 风险。因此,达罗鲁胺与上述UGT代谢的药物联合用药时应谨慎,以避免出现潜在的DDIs。
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来源期刊
CiteScore
7.70
自引率
3.90%
发文量
410
审稿时长
36 days
期刊介绍: Chemico-Biological Interactions publishes research reports and review articles that examine the molecular, cellular, and/or biochemical basis of toxicologically relevant outcomes. Special emphasis is placed on toxicological mechanisms associated with interactions between chemicals and biological systems. Outcomes may include all traditional endpoints caused by synthetic or naturally occurring chemicals, both in vivo and in vitro. Endpoints of interest include, but are not limited to carcinogenesis, mutagenesis, respiratory toxicology, neurotoxicology, reproductive and developmental toxicology, and immunotoxicology.
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