pnu-200577 and mirabegron

To examine the effect of combining a nonselective muscarinic receptor antagonist, 5-hydroxymethyl tolterodine (an active metabolite of fesoterodine), with a β3 adrenoceptor agonist, mirabegron, in a rat model of pelvic congestion.. The rat pelvic congestion model used female Sprague-Dawley rats with their bilateral common iliac and uterine veins ligated. Expressions of M2 and M3 receptor subtypes in the urothelium and detrusor were detected by real-time polymerase chain reaction assays. The effects of both drugs were investigated on isolated bladder strips contracted by electrical field stimulation. in vivo single cystometry was used to assess the effects of 5-hydroxymethyl tolterodine and mirabegron independently or in combination on bladder capacity, micturition pressure, and threshold pressure.. Pelvic congestion rats showed decreased bladder capacity compared with controls, but micturition pressure and threshold pressure were unchanged. Pelvic congestion model rats also demonstrated an approximately two-fold increase in expression of both M2 and M3 receptor subtypes in the urothelium. Additive relaxant effects of 5-hydroxymethyl tolterodine and mirabegron were observed in vitro in the electrical field stimulation-induced contractions of bladder strips from pelvic congestion rats. In vivo, bladder capacity was increased significantly by a combination of 5-hydroxymethyl tolterodine and mirabegron, with the combined effect exceeding the sum of the effects of monotherapies. Micturition pressure and threshold pressure did not significantly differ between groups.. The combination of 5-hydroxymethyl tolterodine with mirabegron suggests the potential of synergistic effects in a rat pelvic congestion model.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Benzhydryl Compounds; Cresols; Disease Models, Animal; Drug Monitoring; Drug Therapy, Combination; Female; Muscarinic Antagonists; Rats; Rats, Sprague-Dawley; Thiazoles; Treatment Outcome; Urinary Bladder, Overactive

5-Hydroxymethyl tolterodine (5-HMT; the active fesoterodine metabolite) is metabolized via the cytochrome P450 (CYP) 2D6 and CYP3A pathways. Mirabegron is a moderate CYP2D6 inhibitor and weak CYP3A inhibitor. Potential drug-drug interactions (DDIs) following coadministration of these 2 overactive bladder treatments were estimated using physiologically based pharmacokinetic models, developed and verified by comparing predicted and observed pharmacokinetic profiles from clinical studies. Models predicted and verified mirabegron and desipramine (CYP2D6 substrate) and 5-HMT and ketoconazole (strong CYP3A inhibitor) DDIs. Mirabegron model-predicted mean steady-state AUC and C

Topics: Acetanilides; Adult; Benzhydryl Compounds; Cresols; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Female; Humans; Ketoconazole; Male; Middle Aged; Rifampin; Thiazoles; Urinary Bladder, Overactive

Mirabegron, the first selective β

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Benzhydryl Compounds; Cresols; Drug Interactions; Female; Healthy Volunteers; Humans; Middle Aged; Postmenopause; Thiazoles; Tolterodine Tartrate; Urological Agents