Mirabegron: potential off target effects and uses beyond the bladder

Abstract

This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.

Acute metabolic and cardiovascular effects of mirabegron in healthy individuals

“…This mechanism explains the increase in heart rate after the 200‐mg dose . This ionotropic action of mirabegron is similar to the sympathomimetic ephedrine; both compounds share a phenylethanolamine structure, which is sensitive to sympathetic nerve terminal uptake and induction of noradrenaline release . The subsequent result is an increase in the rate and/or force of contraction of the heart, thereby increasing blood pressure …”

“…33 This ionotropic action of mirabegron is similar to the sympathomimetic ephedrine; both compounds share a phenylethanolamine structure, which is sensitive to sympathetic nerve terminal uptake and induction of noradrenaline release. 32,34,35 The subsequent result is an increase in the rate and/or force of contraction of the heart, thereby increasing blood pressure. 36,37 In addition to mirabegron's indirect effects on the β1-adrenoceptor, it is also suggested to have a high binding affinity with muscarinic receptors and to antagonise α1-adrenoceptors in human and isolated rat tissue binding/functional experiments.…”

Agonist‐induced desensitisation of β3‐adrenoceptors: Where, when, and how?

“…Based on known β 3 -adrenoceptor functions, it is anticipated that potential clinical uses of ligands for this subtype will be limited to agonists (Dehvari, da Silva Junior, Bengtsson, & Hutchinson, 2018;Michel, Ochodnicky, & Summers, 2010). For such uses, a relative resistance to desensitisation is likely to be a desirable property.…”

Efficacy of novel β3‐adrenoreceptor agonist vibegron on nocturia in patients with overactive bladder: A post‐hoc analysis of a randomized, double‐blind, placebo‐controlled phase 3 study

“…Mirabegron, a CYP2D6 inhibitor, has been reported to have off‐target effects, whereas vibegron is metabolized independently from CYP3A4, 2D6 or 2C9, and is thus considered less likely to cause drug–drug interactions. Vibegron is also reported to be highly selective to cardiac ion channels (hERG, hCav1.2 and hNav1.5) and serotonin transporters …”

“…Although no head-to-head comparison data are available between vibegron and mirabegron, the above data suggest that the presence/absence of pretreatment might have influenced the effects of vibegron and mirabegron on the frequency of nocturnal voiding. Mirabegron, a CYP2D6 inhibitor, has been reported to have off-target effects, 27 whereas vibegron is metabolized independently from CYP3A4, 2D6 or 2C9, and is thus considered less likely to cause drug-drug interactions. Vibegron is also reported to be highly selective to cardiac ion channels (hERG, hCav1.2 and hNav1.5) and serotonin transporters.…”