Farmakologické vlastnosti, účinky a rizika

Binding to the beta 3-adrenergic receptor

• Bind deep in the binding pocket of the receptors
• Exhibit some H-bonds and or hydrophobic interactions with the receptor [1 ]

Bioavailability of Mirabegron

• 29%-35% [1]

Distribuce of Mirabegron

• Cca 71% of Mirabegron is bound to the human plasma proteins [1]

Half-life of Mirabegron

• Cca 50 h [1]

Metabolism of Mirabegron

• Via multiple pathways involving
• Oxidation
• Amide hydrolysis
• (direct) glucuronidation
• Dealkylation
• Butyrylcholinesterase is also participant
• Excreted
• 55% in urine
• 34% in faeces, mainly in unchanged form [1]

Steady state of Mirabegron

• Reached after 7 days p.o. 1xd [1]

Basic structure of beta 3-adrenergic receptor agonists

• 2-amino-1-phenylethan-1-ol
• Have variations that affect the selectivity of the agonist [1 ]
• Most of the selective agonists
• Have an aromatic ring formation
• Or another hydrophobic region, around 2-3 carbons from the central protonated amine group
• Interacts with the superficial extracellular (ELC2) domain on the receptor
• Interactions affect the ability of the ligand to align properly in the deep binding pocket
• Important factor for the total affinity of the ligand [1 ]

Struktura Solabegronu

Synthesis of Mirabegron

• Major limitation is the possible formation of significant amount of undesired side products
• And tedious chromatographic purification [1]

Nežádoucí účinky

• Adverse effects in some particular types of beta-3 adrenergic receptor agonists (FDA 2012; Nitti 2013)
• Hypertension
• Nasopharyngitis
• Urinary tract infection
• Headache [12]
• High doses of unspecific agonists producing opposing positive inotropic effects
• Control for reflex orthosympathetic reaction to intense peripheral vasodilatation [12]