Recent progress and challenges in screening and characterization of UGT1A1 inhibitors

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.

Metabolism and disposition of corylifol A from Psoralea corylifolia: metabolite mapping, isozyme contribution, species differences and identification of efflux transporters for corylifol A-O-glucuronide in HeLa1A1 cells

“…Similarly, several UGT1A1 substrates, like endogenous estradiol, bilirubin and clinical irinotecan, morphine, ezetimibe, all could be inhibited by CA and CA-containing herbal medicines, inducing clinical adverse reactions. Therefore, greater attention should be paid to avoid the potential risks of herbal medicines-drug interactions by considering the inhibitory effects of bioactive compounds on several human CYPs and UGTs (Lv et al, 2019;Zhou et al, 2019).…”

Identifying the reactive metabolites of tyrosine kinase inhibitors in a comprehensive approach: Implications for drug‐drug interactions and hepatotoxicity

“…144 UGT1A1 inhibition has been suggested as the most likely cause of hyperbilirubinemia for several TKI. 143 Regorafenib and sorafenib were shown to strongly inhibit UGT1A1-mediated bilirubin glucuronidation which could have a significant effect on UGT1A1 activity in vivo, contrary to lapatinib and pazopanib. 145 Sorafenib, imatinib, and dasatinib were reported to inhibit UGT1A9-mediated paracetamol glucuronidation in vitro, inhibitions being also predicted to occur in vivo for sorafenib and imatinib.…”

“…Particular attention is payed to UGT1A1 because of its involvement in bilirubin glucuronidation and its large interindividual variability due to UGT1A1*28 polymorphism . Regulatory agencies have thus recommended to assay the potential of new drugs to inhibit UGT1A1 prior approval to predict clinical hyperbilirubinemia . UGT1A1 inhibition has been suggested as the most likely cause of hyperbilirubinemia for several TKI .…”

“…Regulatory agencies have thus recommended to assay the potential of new drugs to inhibit UGT1A1 prior approval to predict clinical hyperbilirubinemia . UGT1A1 inhibition has been suggested as the most likely cause of hyperbilirubinemia for several TKI . Regorafenib and sorafenib were shown to strongly inhibit UGT1A1‐mediated bilirubin glucuronidation which could have a significant effect on UGT1A1 activity in vivo, contrary to lapatinib and pazopanib .…”

An investigation of the metabolic activity, isozyme contribution, species differences and potential drug–drug interactions of PI-103, and the identification of efflux transporters for PI-103-O-glucuronide in HeLa1A9 cells

“…[10][11][12] Inhibition of human CYP or UGT functions can not only trigger potentially adverse clinical DDIs, but could also result in metabolic disorders for endogenous molecules. [13][14][15] Considering the potential co-administration of PI-103 with other chemotherapeutic drugs, it is crucial to evaluate the potential risks of DDI in clinics.…”