Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202
© 2019 We have demonstrated previously that the kinase inhibitors (KIs) lapatinib, pazopanib, regorafenib and sorafenib are potent inhibitors of UGT1A1 and UGTs 1A7-1A10. The present study characterised the effects of four additional drugs in this class, dabrafenib, ibrutinib, nintedanib and trameti...
Saved in:
Main Authors: | , , , , |
---|---|
Other Authors: | |
Format: | Article |
Published: |
2020
|
Subjects: | |
Online Access: | https://repository.li.mahidol.ac.th/handle/123456789/50041 |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Institution: | Mahidol University |
id |
th-mahidol.50041 |
---|---|
record_format |
dspace |
spelling |
th-mahidol.500412020-01-27T14:36:28Z Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202 Porntipa Korprasertthaworn Nuy Chau Pramod C. Nair Andrew Rowland John O. Miners Flinders University Mahidol University Biochemistry, Genetics and Molecular Biology © 2019 We have demonstrated previously that the kinase inhibitors (KIs) lapatinib, pazopanib, regorafenib and sorafenib are potent inhibitors of UGT1A1 and UGTs 1A7-1A10. The present study characterised the effects of four additional drugs in this class, dabrafenib, ibrutinib, nintedanib and trametinib, on human UGT enzyme activities in vitro. Dabrafenib, ibrutinib, nintedanib and trametinib were potent inhibitors of human liver microsomal UGT1A1; Ki,u values ranged from 1.1 to 7.5 µM. Similarly, these KIs inhibited UGT 1A7, 1A8, 1A9 and 1A10, albeit less potently than UGT1A1. Despite the potent inhibition of UGT1A1, in vitro – in vivo extrapolation excluded the likelihood that dabrafenib, ibrutinib, nintedanib and trametinib would precipitate drug-drug interactions (DDIs) due to the low unbound plasma concentrations of these drugs observed in patients. The structures of dabrafenib, ibrutinib, lapatinib, nintedanib, pazopanib, regorafenib, trametinib and 22 other KIs overlaid well on that of sorafenib, a potent inhibitor of UGT1A1 and UGTs 1A7-1A10. Taken together, kinetic and computational modelling data suggest that all currently marketed KIs are likely to be potent inhibitors of UGT1A1, and are also likely to inhibit UGTs 1A7-1A10 to some extent due to the structural and chemical features shared in common by these drugs. By contrast, BIBF 1202, the major metabolite of nintedanib, did not appreciably inhibit human UGTs, due to the presence of a terminal electronegative group which appears to disfavor enzyme inhibition. Given the potent inhibition of several UGT enzymes, especially UGT1A1, by KIs, characterisation of the DDI potential of newly developed agents in this class is warranted. 2020-01-27T07:36:28Z 2020-01-27T07:36:28Z 2019-11-01 Article Biochemical Pharmacology. Vol.169, (2019) 10.1016/j.bcp.2019.08.018 18732968 00062952 2-s2.0-85072302125 https://repository.li.mahidol.ac.th/handle/123456789/50041 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85072302125&origin=inward |
institution |
Mahidol University |
building |
Mahidol University Library |
continent |
Asia |
country |
Thailand Thailand |
content_provider |
Mahidol University Library |
collection |
Mahidol University Institutional Repository |
topic |
Biochemistry, Genetics and Molecular Biology |
spellingShingle |
Biochemistry, Genetics and Molecular Biology Porntipa Korprasertthaworn Nuy Chau Pramod C. Nair Andrew Rowland John O. Miners Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202 |
description |
© 2019 We have demonstrated previously that the kinase inhibitors (KIs) lapatinib, pazopanib, regorafenib and sorafenib are potent inhibitors of UGT1A1 and UGTs 1A7-1A10. The present study characterised the effects of four additional drugs in this class, dabrafenib, ibrutinib, nintedanib and trametinib, on human UGT enzyme activities in vitro. Dabrafenib, ibrutinib, nintedanib and trametinib were potent inhibitors of human liver microsomal UGT1A1; Ki,u values ranged from 1.1 to 7.5 µM. Similarly, these KIs inhibited UGT 1A7, 1A8, 1A9 and 1A10, albeit less potently than UGT1A1. Despite the potent inhibition of UGT1A1, in vitro – in vivo extrapolation excluded the likelihood that dabrafenib, ibrutinib, nintedanib and trametinib would precipitate drug-drug interactions (DDIs) due to the low unbound plasma concentrations of these drugs observed in patients. The structures of dabrafenib, ibrutinib, lapatinib, nintedanib, pazopanib, regorafenib, trametinib and 22 other KIs overlaid well on that of sorafenib, a potent inhibitor of UGT1A1 and UGTs 1A7-1A10. Taken together, kinetic and computational modelling data suggest that all currently marketed KIs are likely to be potent inhibitors of UGT1A1, and are also likely to inhibit UGTs 1A7-1A10 to some extent due to the structural and chemical features shared in common by these drugs. By contrast, BIBF 1202, the major metabolite of nintedanib, did not appreciably inhibit human UGTs, due to the presence of a terminal electronegative group which appears to disfavor enzyme inhibition. Given the potent inhibition of several UGT enzymes, especially UGT1A1, by KIs, characterisation of the DDI potential of newly developed agents in this class is warranted. |
author2 |
Flinders University |
author_facet |
Flinders University Porntipa Korprasertthaworn Nuy Chau Pramod C. Nair Andrew Rowland John O. Miners |
format |
Article |
author |
Porntipa Korprasertthaworn Nuy Chau Pramod C. Nair Andrew Rowland John O. Miners |
author_sort |
Porntipa Korprasertthaworn |
title |
Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202 |
title_short |
Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202 |
title_full |
Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202 |
title_fullStr |
Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202 |
title_full_unstemmed |
Inhibition of human UDP-glucuronosyltransferase (UGT) enzymes by kinase inhibitors: Effects of dabrafenib, ibrutinib, nintedanib, trametinib and BIBF 1202 |
title_sort |
inhibition of human udp-glucuronosyltransferase (ugt) enzymes by kinase inhibitors: effects of dabrafenib, ibrutinib, nintedanib, trametinib and bibf 1202 |
publishDate |
2020 |
url |
https://repository.li.mahidol.ac.th/handle/123456789/50041 |
_version_ |
1763488445546627072 |