Recent progress and challenges in screening and characterization of UGT1A1 inhibitors

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Lv , X , Xia , Y , Finel , M , Wu , J , Ge , G & Yang , L 2019 , ' Recent progress and challenges in screening and characterization of UGT1A1 inhibitors ' , Acta pharmaceutica sinica b , vol. 9 , no. 2 , pp. 258-278 . https://doi.org/10.1016/j.apsb.2018.09.005

Title: Recent progress and challenges in screening and characterization of UGT1A1 inhibitors
Author: Lv, Xia; Xia, Yangliu; Finel, Moshe; Wu, Jingjing; Ge, Guangbo; Yang, Ling
Contributor: University of Helsinki, Division of Pharmaceutical Chemistry and Technology
Date: 2019-03
Language: eng
Number of pages: 21
Belongs to series: Acta pharmaceutica sinica b
ISSN: 2211-3835
URI: http://hdl.handle.net/10138/300497
Abstract: Uridine-diphosphate glucuronosyltransferase 1A1 (UGT1A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1A1 may trigger adverse drug/herb-drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1A1 prior to approval. This review focuses on the significance, progress and challenges in discovery and characterization of UGT1A1 inhibitors. Recent advances in the development of UGT1A1 probes and their application for screening UGT1A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects via UGT1A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1A1 inhibitors and for facilitating investigations on UGT1A1-ligand interactions. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
Subject: UGT1A1 inhibitors
Drug/herbdrug interactions
Probe substrates
High-throughput screening
UDP-GLUCURONOSYLTRANSFERASE 1A1
HUMAN LIVER-MICROSOMES
RATIOMETRIC FLUORESCENT-PROBE
PRIMARY HUMAN HEPATOCYTES
HUMAN CARBOXYLESTERASE 2
IN-VITRO INHIBITION
BILIRUBIN GLUCURONIDATION
GENETIC-POLYMORPHISM
DRUG-INTERACTIONS
ENZYME-ACTIVITIES
116 Chemical sciences
317 Pharmacy
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