Identification of Uridine 5'-Diphosphate-Glucuronosyltransferases Responsible for the Glucuronidation of Mirabegron, a Potent and Selective beta3-Adrenoceptor Agonist, in Human Liver Microsomes.
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Konishi K, Tenmizu D, Takusagawa S
Identification of Uridine 5'-Diphosphate-Glucuronosyltransferases Responsible for the Glucuronidation of Mirabegron, a Potent and Selective beta3-Adrenoceptor Agonist, in Human Liver Microsomes.
Eur J Drug Metab Pharmacokinet. 2018 Jun;43(3):301-309. doi: 10.1007/s13318-017-0450-x.
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- 29164523 [ View in PubMed]
- Abstract
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 muM mirabegron, 8 mM MgCl2, alamethicin (25 mug/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 muL for 120 min at 37 degrees 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, r (2) = 0.330, p = 0.020) in individual HLMs; inhibition by mefenamic acid in pooled HLMs (IC50 = 22.8 muM); and relatively similar K m values between pooled HLMs and rhUGT2B7 (1260 vs. 486 muM). 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Mirabegron UDP-glucuronosyltransferase 1-3 Protein Humans NoSubstrateDetails Mirabegron UDP-glucuronosyltransferase 1-8 Protein Humans NoSubstrateDetails Mirabegron UDP-glucuronosyltransferase 2B7 Protein Humans NoSubstrateDetails - Drug Reactions
Reaction Details Details Details
