title: Identification of human cytochrome P450 isoforms and esterases involved in the metabolism of mirabegron, a potent and selective β3-adrenoceptor agonist.
abstract: 1. Human cytochrome P450 (CYP) enzymes and esterases involved in the metabolism of mirabegron, a potent and selective human β(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 6β-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 μM). The inhibition profiles in human blood and plasma were also similar to those in BChE solution, suggesting that mirabegron hydrolysis is catalyzed by BChE.
authors.affiliation: Drug Metabolism Research Laboratories, Astellas Pharma Inc., Osaka, Japan. shin.takusagawa@astellas.com
authors.forename: Shin
authors.initials: S
authors.lastname: Takusagawa
authors.forename: Kanako
authors.initials: K
authors.lastname: Yajima
authors.forename: Aiji
authors.initials: A
authors.lastname: Miyashita
authors.forename: Shotaro
authors.initials: S
authors.lastname: Uehara
authors.forename: Takafumi
authors.initials: T
authors.lastname: Iwatsubo
authors.forename: Takashi
authors.initials: T
authors.lastname: Usui
mesh_terms: D000083:Acetanilides / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D000110:Acetylcholinesterase / Q000378:metabolism; D058667:Adrenergic beta-3 Receptor Agonists / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000378:metabolism; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004950:Esterases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D007106:Immune Sera / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010105:Oxygenases / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012996:Solutions; D013844:Thiazoles / Q000097:blood / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D000911:Antibodies, Monoclonal; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D065692:Cytochrome P-450 CYP3A Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D018076:DNA, Complementary; D007106:Immune Sera; D007527:Isoenzymes; D022702:Receptors, Adrenergic, beta-3; D011994:Recombinant Proteins; D012996:Solutions; D013844:Thiazoles; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; D004950:Esterases; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C520025:mirabegron