Bladder selectivity of the novel β3-agonist ritobegron (KUC-7483) explored by in vitro and in vivo studies in the rat

Abstract

We performed in vitro and in vivo experiments to evaluate the pharmacological profile of ritobegron and its effects on the bladder in rats. β(3)-AR selectivity was assessed using CHO cells expressing various subtypes of the human β-adrenoceptor (AR). Effects on isolated organs were evaluated using the organ-bath method. Effects on intravesical pressure, heart rate, and mean blood pressure were evaluated in urethane-anesthetized rats. Ritobegron increased cAMP accumulation in a concentration-dependent manner in CHO cells expressing any one of three human β-AR, its selectivity for β(3)-AR being 301-fold and 32-fold higher versus β(1)-AR and β(2)-AR, respectively. Ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50), 7.7 × 10(-8) mol/L; maximal relaxation, 97.0 %), and the β(3)-AR antagonist SR58894A produced a parallel rightward-shift of this concentration-response curve without altering the maximal response [pK(B) value, 6.43]. Ritobegron concentration-dependently increased atrial rate and decreased myometrial contractions in vitro, and its selectivity for the bladder was 2,078-fold higher versus the atria and 14-fold higher versus the uterus. In vivo, ritobegron induced a dose-dependent decrease in intravesical pressure (ED(50) 0.4 mg/kg), without affecting heart rate and only slightly lowering mean blood pressure. Thus, ritobegron displayed potent and selective β(3)-AR agonistic activity toward transfected human β-AR and exhibited a high selectivity for the bladder versus other organs in rats. Moreover, it decreased intravesical pressure with minimal effects on the cardiovascular system in anesthetized rats. These results suggest that ritobegron shows promise as a potential agent for the treatment of overactive bladder.

Functional investigation of β-adrenoceptors in human isolated detrusor focusing on the novel selective β3-adrenoceptor agonist KUC-7322

“…In two series of experiments performed with similar protocols but with bladder strips from Japanese and German patients, we have demonstrated that KUC-7322 is 0.7-1.0 log units less potent than the reference agonist isoproterenol but has a comparable efficacy. These findings are in line with findings for rat detrusor relaxation, where KUC-7322 also was slightly less potent but similarly efficacious as isoproterenol (Maruyama et al 2012). In rats, these in vitro findings translated into a dosedependent reduction of intravesicular pressure in anesthetized animals in vivo by ritobegron, the prodrug of KUC-7322 (Maruyama et al 2012).…”

“…KUC-7322 is the active metabolite of ritobegron (also known as and was reported to be 301-and 32-fold selective for β3-AR over β1-AR and β2-AR for stimulation of cAMP formation by cloned human receptor subtypes; a similar selectivity profile was obtained by comparing its potency for relaxation of rat bladder as compared to rat atrium and myometrium (Maruyama et al 2012). In two series of experiments performed with similar protocols but with bladder strips from Japanese and German patients, we have demonstrated that KUC-7322 is 0.7-1.0 log units less potent than the reference agonist isoproterenol but has a comparable efficacy.…”

“…Ritobegron (also known as KUC-7483) is a novel compound developed in the search for a promising drug for overactive bladder syndromes carried out by Kissei Pharmaceutical Co. Ltd. After oral administration, KUC-7483 is rapidly converted to KUC-7322, a selective β3-AR agonist (Maruyama et al 2012). It was recently reported (a) that KUC-7322 has selective agonistic activity for the human β3-AR and a potent relaxing effect on the isolated rat bladder via stimulation of β3-AR and (b) that it decreases intravesical pressure in rats with minimal effects on the cardiovascular system (Maruyama et al 2012). In the present study, we characterized the β-AR subtype mediating human detrusor relaxation based on agonists and antagonists and determined the ability of KUC-7322 to cause relaxation and to prevent contraction of isolated human detrusor.…”

Investigation of Drug–Drug Interactions Between Ritobegron, a Selective β3‐Adrenoceptor Agonist, With Probenecid in Healthy Men

“…Before this study, we were apprehensive that an increase in exposure of KUC-7322 might affect ECG parameters such as the heart rate and QT interval because KUC-7322 is a weak b 1 -and b 2-adrenoceptors agonist, even though it is highly selective for the b 3 -adrenoceptor; the selectivity of KUC-7322 for b 1 -and b 2-adrenoceptors is 1/301 and 1/32, respectively, of that for the b 3 -adrenoceptor. 6 Although an increase in exposure and a decrease in clearance were observed following coadministration of probenecid, there were no clinically significant abnormal ECG changes in this study. Furthermore, there were no obvious differences in subjective/objective findings, vital signs (blood pressure, pulse rate, and temperature), physical examinations (body weight), and clinical laboratory values (hematology, blood chemistry, and urinalysis) between ritobegron alone and ritobegron in combination with probenecid.…”

“…To measure the KUC-7322 concentrations, blood samples (2 mL per time) were collected in vacuum blood collection tubes containing ethylenediaminetetraacetic acid disodium salt, sodium fluoride, and heparin at the following times after administration of ritobegron: 0.25, 0.5, 1, 1.5, 2, 3, 4,6,8,12,14,24,36, and 48 hours. Blood samples were centrifuged (3000 rpm) at 4˚C for 10 minutes and separated.…”