title: In vitro inhibition and induction of human cytochrome P450 enzymes by mirabegron, a potent and selective β3-adrenoceptor agonist.
abstract: The potential for mirabegron, a β(3)-adrenoceptor agonist for the treatment of overactive bladder, to cause drug-drug interactions via inhibition or induction of cytochrome P450 (CYP) enzymes was investigated in vitro.        Mirabegron was shown to be a time-dependent inhibitor of CYP2D6 in the presence of NADPH as the IC(50) value in human liver microsomes decreased from 13 to 4.3 μM after 30-min pre-incubation. Further evaluation indicated that mirabegron may act partly as an irreversible or quasi-irreversible metabolism-dependent inhibitor of CYP2D6. Therefore, the potential of mirabegron to inhibit the metabolism of CYP2D6 substrates in vivo cannot be excluded. Mirabegron was predicted not to cause clinically significant metabolic drug-drug interactions via inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A4/5 because the IC(50) values for these enzymes both with and without pre-incubation were >100 μM (370 times maximum human plasma concentration [C(max)]).        Whereas positive controls (100 µM omeprazole and 10 µM rifampin) caused the anticipated CYP induction, the highest concentration of mirabegron (10 µM; 37 times plasma C(max)) had minimal effect on CYP1A2 and CYP3A4/5 activity, and CYP1A2 and CYP3A4 mRNA levels in freshly isolated human hepatocytes, suggesting that mirabegron is not an inducer of these enzymes.
authors: Drug Metabolism Research Laboratories, Astellas Pharma Inc., Osaka , Japan. shin.takusagawa@astellas.com
authors: Shin
authors: S
authors: Takusagawa
authors: Aiji
authors: A
authors: Miyashita
authors: Takafumi
authors: T
authors: Iwatsubo
authors: Takashi
authors: T
authors: Usui
mesh_terms: D000083:Acetanilides / Q000737:chemistry / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013844:Thiazoles; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; C520025:mirabegron