Identification of human cytochrome P450 isoforms and esterases involved in the metabolism of mirabegron, a potent and selective beta3-adrenoceptor agonist.
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Takusagawa S, Yajima K, Miyashita A, Uehara S, Iwatsubo T, Usui T
Identification of human cytochrome P450 isoforms and esterases involved in the metabolism of mirabegron, a potent and selective beta3-adrenoceptor agonist.
Xenobiotica. 2012 Oct;42(10):957-67. doi: 10.3109/00498254.2012.675095. Epub 2012 Apr 18.
- PubMed ID
- 22509825 [ View in PubMed]
- Abstract
1. Human cytochrome P450 (CYP) enzymes and esterases involved in the metabolism of mirabegron, a potent and selective human beta(3)-adrenoceptor agonist intended for the treatment of overactive bladder, were identified in in vitro studies. 2. Incubations of mirabegron with recombinant human CYP enzymes showed significant metabolism of mirabegron by CYP2D6 and CYP3A4 only. Correlation analyses showed a significant correlation between mirabegron metabolism and testosterone 6beta-hydroxylation (CYP3A4/5 marker activity). In inhibition studies using antiserum against CYP3A4, a strong inhibition (at maximum 80% inhibition) of the metabolism of mirabegron was observed, whereas the inhibitory effects of monoclonal antibodies against CYP2D6 were small (at maximum 10% inhibition). These findings suggest that CYP3A4 is the primary CYP enzyme responsible for in vitro oxidative metabolism of mirabegron, with a minor role of CYP2D6. 3. Mirabegron hydrolysis was catalyzed in human blood, plasma and butyrylcholinesterase (BChE) solution, but not in human liver microsomes, intestinal microsomes, liver S9, intestinal S9 and recombinant acetylcholinesterase solution. K(m) values of mirabegron hydrolysis in human blood, plasma and BChE solution were all similar (13.4-15.2 muM). The inhibition profiles in human blood and plasma were also similar to those in BChE solution, suggesting that mirabegron hydrolysis is catalyzed by BChE.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Mirabegron Cholinesterase Protein Humans NoSubstrateDetails Mirabegron Cytochrome P450 2D6 Protein Humans NoSubstrateInhibitorDetails Mirabegron Cytochrome P450 3A4 Protein Humans NoSubstrateDetails