Muscarinic Receptor Binding Activity in Rat Tissues by Vibegron and Prediction of Its Receptor Occupancy Levels in the Human Bladder.

Objectives To examine the effects of vibegron, a selective beta(3)-adrenoceptor agonist, used to treat overactive bladder, on muscarinic receptors in the rat bladder, and to predict the occupancy levels of muscarinic receptors by vibegron in the bladders of humans orally administered a clinical dose. Methods Muscarinic receptors in the rat bladder and other tissues were examined by a radioligand binding assay using [N-methyl-H-3]scopolamine chloride. The occupancy levels of muscarinic receptors by vibegron in bladders of humans after its oral administration were predicted from the estimation of unbound concentrations in human plasma and urine in the literature. Results Vibegron (0.1-100 mu mol/L) inhibited specific [N-methyl-H-3]scopolamine chloride binding in the bladder and other tissues of rats in a concentration-dependent manner. The 50% inhibitory concentration value of vibegron in the bladder was approximately twofold higher than that in the heart, and approximately 315- and 3.5-fold lower than those in the submaxillary gland and brain, respectively. Therefore, the binding affinity of vibegron for muscarinic receptors was higher in the heart and bladder than in the submaxillary gland and brain. By using the rat bladder receptor binding affinity, occupancy levels of muscarinic receptors in the human bladder were predicted to be 51-91% until 24 h after its oral administration at 50 mg of vibegron. Conclusions This is the first study to suggest that vibegron binds to muscarinic receptors in the rat bladder and other tissues, with a potentially higher affinity for the M-2 subtype than the M-1 and M-3 subtypes. These results might be clinically relevant for pharmacotherapy with vibegron for overactive bladder.