1365244-68-3Relevant articles and documents
Identification of Uridine 5′-Diphosphate-Glucuronosyltransferases Responsible for the Glucuronidation of Mirabegron, a Potent and Selective β3-Adrenoceptor Agonist, in Human Liver Microsomes
Konishi, Kentaro,Tenmizu, Daisuke,Takusagawa, Shin
, p. 301 - 309 (2018)
Background and Objectives: Mirabegron is cleared by multiple mechanisms, including drug-metabolizing enzymes. One of the most important clearance pathways is direct glucuronidation. In humans, M11 (O-glucuronide), M13 (carbamoyl-glucuronide), and M14 (N-glucuronide) have been identified, of which M11 is one of the major metabolites in human plasma. The objective of this study was to identify the uridine 5′-diphosphate (UDP)-glucuronosyltransferase (UGT) isoform responsible for the direct glucuronidation of mirabegron using human liver microsomes (HLMs) and recombinant human UGTs (rhUGTs). Methods: Reaction mixtures contained 1–1000?μM mirabegron, 8?mM MgCl2, alamethicin (25?μg/mL), 50?mM Tris–HCl buffer (pH 7.5), human liver microsome?(HLM) or rhUGT (1.0?mg protein/mL), and 2?mM UDP-glucuronic acid in a total volume of 200?μL for 120?min at 37?°C. HLMs from 16 individuals were used for the correlation study, and mefenamic acid and propofol were used for the inhibition study. Results: Regarding M11 formation, rhUGT2B7 showed high activity among the rhUGTs tested (11.3?pmol/min/mg protein). This result was supported by the correlation between M11 formation activity and UGT2B7 marker enzyme activity (3-glucuronidation of morphine, r2?=?0.330, p?=?0.020) in individual HLMs; inhibition by mefenamic acid in pooled HLMs (IC50?=?22.8?μM); and relatively similar Km values between pooled HLMs and rhUGT2B7 (1260 vs. 486?μM). Regarding M13 and M14 formation, rhUGT1A3 and rhUGT1A8 showed high activity among the rhUGTs tested, respectively. Conclusions: UGT2B7 is the main catalyst of M11 formation in HLMs. Regarding M13 and M14 formation, UGT1A3 and UGT1A8 are strong candidates for glucuronidation, respectively.
