Muscarinic Receptor Binding and Plasma Drug Concentration after the Oral Administration of Propiverine in Mice

Objectives: The current study was undertaken to characterize the binding of propiverine to muscarinic receptors in mouse tissues by measuring plasma concentrations of the drug and its metabolite.

Methods: At 0.5-24 h after the oral administration of propiverine at pharmacologically relevant doses, muscarinic receptors in tissue homogenates were measured by a radioligand binding assay using [N-methyl- (3) H]scopolamine (NMS), along with the drug's concentration in plasma by the liquid chromatography-tandem mass spectrometric method.

Results: In the in vitro experiments, propiverine and its metabolite 1-methy-4-piperidyl benzilate N-oxide competed with [(3) H]NMS for binding sites in the bladder, submaxillary gland and heart of mice in a concentration-dependent manner. After the oral administration of propiverine, dose- and time-dependent increases in the dissociation constant for specific [(3) H]NMS binding were observed in the bladder and other tissues of mice, indicating that orally administered propiverine and/or its metabolite undergo significant binding to muscarinic receptors in mouse tissues. A longer-lasting binding of muscarinic receptor was seen in the bladder than in the submaxillary gland at relatively low doses of propiverine. Furthermore, the decrease in maximal number of binding sites values for [(3) H]NMS binding was more remarkable in the bladder than submaxillary gland of propiverine treated mice. There was a dose-dependent rise in the plasma concentrations of propiverine and 1-methy-4-piperidyl benzilate N-oxide in mice after the oral administration of propiverine.

Conclusion: The oral administration of propiverine exerts a more prominent and longer-lasting effect in the bladder than in the submaxillary gland of mice. The N-oxide metabolite may contribute significantly to the blockade of muscarinic receptors caused by oral propiverine.