Takusagawa_2012_Xenobiotica_42_957

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 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 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.