Contributions of UDP-Glucuronosyltransferases to Human Hepatic and Intestinal Metabolism of Ticagrelor and Inhibition of UGTs and Cytochrome P450 Enzymes by Ticagrelor and its Glucuronidated Metabolite
Ticagrelor is the first reversibly binding, direct-acting, oral P2Y 12 receptor inhibitor. The contribution of UDP-glucuronosyltransferases (UGTs) enzymes to the metabolism of ticagrelor to its glucuronide conjugation, ticagrelor-O-glucuronide, in human liver microsomes (HLM) and human intestinal mi...
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Published in | Frontiers in pharmacology Vol. 12; p. 761814 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
14.10.2021
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Subjects | |
Online Access | Get full text |
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Summary: | Ticagrelor is the first reversibly binding, direct-acting, oral P2Y
12
receptor inhibitor. The contribution of UDP-glucuronosyltransferases (UGTs) enzymes to the metabolism of ticagrelor to its glucuronide conjugation, ticagrelor-O-glucuronide, in human liver microsomes (HLM) and human intestinal microsomes (HIM), was well characterized in the current study. The inhibition potential of human major UGTs by ticagrelor and ticagrelor-O-glucuronide was explored. The inhibitory effects of ticagrelor-O-glucuronide on cytochrome P450s (CYPs) enzymes were investigated as well. Ticagrelor glucuronidation exhibits substrate inhibition kinetics in both HLM and HIM with apparent K
m
values of 5.65 and 2.52 μM, V
max
values of 8.03 and 0.90 pmol min
−1
·mg protein
−1
, K
si
values of 1,343.0 and 292.9 respectively. The
in vitro
intrinsic clearances (
V
max
/
K
m
) for ticagrelor glucuronidation by HLM and HIM were 1.42 and 0.36 μl min
−1
·mg protein
−1
, respectively. Study with recombinant human UGTs suggested that multiple UGT isoforms including UGT1A9, UGT1A7, UGT1A3, UGT1A4, UGT1A1, UGT2B7 and UGT1A8 are involved in the conversion of ticagrelor to ticagrelor-O-glucuronide with UGT1A9 showing highest catalytic activity. The results were further supported by the inhibition studies on ticagrelor glucuronidation with typical UGT inhibitors in pooled HLM and HIM. Little or no inhibition of UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 by ticagrelor and ticagrelor-O-glucuronide was noted. Ticagrelor-O-glucuronide also exhibited limited inhibitory effects toward CYP2C8, CYP2D6 and CYP3A4. In contrast, ticagrelor-O-glucuronide weakly inhibited CYP2B6, CYP2C9 and CYP2C19 activity with apparent IC
50
values of 45.0, 20.0 and 18.8 μM, respectively. The potential of ticagrelor-O-glucuronide to cause drug-drug interactions warrant further study. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Constantin Mircioiu, Carol Davila University of Medicine and Pharmacy, Romania This article was submitted to Drug Metabolism and Transport, a section of the journal Frontiers in Pharmacology Reviewed by: Sabariah Ismail, Universiti Sains Malaysia (USM), Malaysia These authors have contributed equally to this work and share first authorship Edited by: Sabina Passamonti, University of Trieste, Italy |
ISSN: | 1663-9812 1663-9812 |
DOI: | 10.3389/fphar.2021.761814 |