mirabegron and Body-Weight

Mirabegron is a potent and selective β3-adrenoceptor agonist in development for treatment of overactive bladder.. Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91).. After oral dosing (25 - 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F.. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 - 50 mg), but increased more than proportionally after oral dosing (25 - 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.

Topics: Acetanilides; Administration, Oral; Adolescent; Adrenergic beta-3 Receptor Agonists; Adult; Area Under Curve; Biological Availability; Biotransformation; Body Weight; Cross-Over Studies; Female; Humans; Infusions, Intravenous; Linear Models; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Netherlands; Sex Factors; Thiazoles; Urinary Bladder, Overactive; Washington; Young Adult

Topics: 3T3-L1 Cells; Acetanilides; Adipocytes; Adipocytes, Brown; Animals; Body Weight; Diet, High-Fat; Gene Expression Regulation; Glucose; Homeostasis; Male; Mice; Mice, Obese; Obesity; Thiazoles; Uncoupling Protein 1

To evaluate the effects of the beta-3 adrenoceptor agonist, mirabegron in a mouse model of detrusor overactivity induced by obesity.. C57BL/6 male mice were fed with standard chow or high-fat diet for 12 weeks. Lean and obese mice were treated orally with mirabegron (10 mg/kg/day) from the last 2 weeks of diet. Cystometric evaluations, functional assays, protein expression for phosphodiesterase type 4 (PDE4), and cyclic adenosine monophosphate (cAMP) measurement were carried out.. In obese mice the body weight, epididymal fat mass, fasting glucose, and low-density lipoprotein (LDL) levels were higher (P < 0.001) than in the lean mice. A reduction of 34% and 54% and an increase of 35% in the epididimal fat, LDL, and HDL levels (P < 0.05), respectively, were observed in the obese group treated with mirabegron, whereas no changes were seen in the lipid profile from lean mice. Obese group showed irregular micturition pattern, characterized by significant increases in frequency and non-void contractions. Carbachol, potassium chloride, and electrical-field stimulation induced detrusor smooth muscle (DSM) contractions, which were greater in bladders from obese mice than from lean mice. Two-week treatment with mirabegron restored all the contractile response alterations in the DSM. Basal intracellular levels of cAMP were reduced (68%), whereas PDE4 protein expression was increased (54%) in bladder from obese mice. Mirabegron restored the cAMP levels in obese bladder, without changing the PDE4 expression.. Mirabegron was able to completely restore the urinary alterations seen in the bladder from obese mice.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Body Weight; Carbachol; Cyclic AMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Muscle Contraction; Muscle, Smooth; Obesity; Thiazoles; Urinary Bladder; Urinary Bladder, Overactive; Urination