In vitro inhibition and induction of human cytochrome P450 enzymes by mirabegron, a potent and selective β3-adrenoceptor agonist

Abstract

1. The potential for mirabegron, a β₃-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.

2. Mirabegron was shown to be a time-dependent inhibitor of CYP2D6 in the presence of NADPH as the IC₅₀ 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 IC₅₀ values for these enzymes both with and without pre-incubation were >100 μM (370 times maximum human plasma concentration [C_max]).

3. 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.

Keywords::

• Cytochrome P450
• drug interaction
• induction
• inhibition
• mirabegron

Acknowledgements

We gratefully thank Ellen van der Aar, Ph.D. at the former Yamanouchi Europe B.V. for her considerable contribution to the high-throughput CYP inhibition screening part of this study.

Declaration of interest

Shin Takusagawa, Aiji Miyashita, Takafumi Iwatsubo, and Takashi Usui are full time employees of Astellas Pharma Inc.