Inhibition of human UDP-glucuronosyltransferase enzyme by entrectinib: Implications for drug-drug interactions

Hang Yin; Zhe Wang; Xin Lv; Zhen Wang; Ying Wang; Wenxuan Fan; Shuang Li; Lili Jiang; Jun Cao; Yong Liu

doi:10.1016/j.cbi.2024.111023

Inhibition of human UDP-glucuronosyltransferase enzyme by entrectinib: Implications for drug-drug interactions

Chem Biol Interact. 2024 Apr 25:395:111023. doi: 10.1016/j.cbi.2024.111023. Online ahead of print.

Authors

Hang Yin¹, Zhe Wang², Xin Lv¹, Zhen Wang¹, Ying Wang¹, Wenxuan Fan¹, Shuang Li¹, Lili Jiang¹, Jun Cao³, Yong Liu⁴

Affiliations

¹ School of Chemical Engineering, Ocean and Life Sciences, Dalian University of Technology, Panjin, 124221, China.
² School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China.
³ Department of Occupational and Environmental Health, Dalian Medical University, Dalian, 116044, China. Electronic address: caojunly@163.com.
⁴ School of Chemical Engineering, Ocean and Life Sciences, Dalian University of Technology, Panjin, 124221, China. Electronic address: yliu@dlut.edu.cn.

PMID: 38677539
DOI: 10.1016/j.cbi.2024.111023

Abstract

As a new type of oral tyrosine kinase inhibitor, entrectinib can act on multiple targets and exert efficacy and has been approved for the treatment of non-small cell lung cancer (NSCLC) and solid tumors. However, whether entrectinib affects the activities of recombinant human UDP-glucuronosyltransferases (UGTs) remains unclear. Herein, we aimed to investigate the inhibitory effects of entrectinib on human UGTs and to assess the potential risk of causing drug-drug interactions (DDIs) based on the inhibition against UGTs. High-performance liquid chromatography (HPLC) was used to evaluate the inhibitory effects of entrectinib on UGTs according to the product formation rate of UGT substrate with or without entrectinib, and the inhibition kinetics experiment was conducted to assess the inhibitory type of entrectinib on UGTs. Our results showed that entrectinib exhibited extensive inhibitory effects on most human UGTs, and especially inhibited the activities of UGT1A7, UGT1A8, and UGT2B15 with K_i (Inhibition constant) of lower than 5 μM (0.95-4.38 μM). Furthermore, the results from quantitative prediction research suggested that the combination of entrectinib at 600 mg/day with substrates primarily metabolized by hepatic UGT2B15 or intestinal UGT1A7 and UGT1A8 might cause clinical DDIs. Thus, special attention should be paid to avoid adverse reactions induced by DDIs when co-administration of entrectinib and drugs metabolized by UGTs.

Keywords: Drug-drug interactions; Entrectinib; Inhibition; UDP-Glucuronosyltransferase.