Shichao Xiao, Hang Yin, Xin Lv, Zhen Wang, Lili Jiang, Yangliu Xia, Yong Liu
{"title":"Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by darolutamide: Prediction of in vivo drug-drug interactions","authors":"Shichao Xiao, Hang Yin, Xin Lv, Zhen Wang, Lili Jiang, Yangliu Xia, Yong Liu","doi":"10.1016/j.cbi.2024.111246","DOIUrl":null,"url":null,"abstract":"<div><p>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 <em>K</em><sub>i</sub> 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 IC<sub>50</sub> value of 3.84 ± 0.46 μM. In addition, the <em>in vitro-in vivo</em> 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.</p></div>","PeriodicalId":274,"journal":{"name":"Chemico-Biological Interactions","volume":"403 ","pages":"Article 111246"},"PeriodicalIF":4.7000,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemico-Biological Interactions","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0009279724003922","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
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.
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.