Development of therapeutic agents for urinary incontinence by in vivo analysis of dru-receptor binding characteritics

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Anticholinergic agents such as propiverine and oxybutynin (Oxy) are widely used for the treatment of micturition and urge urinary incontinence. However, the use of these drugs is often limited by systemic side effects such as dry mouth known to occur frequently when they were orally administered, and also by short-duration of action. To develop effective agents in the therapy of DI, we characterized muscarinic receptor binding in rat tissues after the oral administration of propiverine and oxybutynin and after the transdermal application of Oxy (MM-801).[Experiment I] : Oral administration of oxybutynin caused a significant increase in the apparent dissociation constant (K_d) for specific (-)-[^3H]QNB binding in the rat bladder, prostate, submaxillary gland, heart and cerebral cortex, compared with each of the control values. Also, in the submaxillary gland of these rats, there was a reduction in the maximal number of binding sites (B_<max>) for (-)-[^3H]QNB binding. Similarly, oral ad … More ministration of propiverine brought about a significant increase in the K_d values for (-)-[^3H] QNB binding in rat tissues including the bladder, and greater increase in K_d values was seen in the rat prostate, heart and submaxillary gland. On the other hand, oral administration of propiverine, unlike oxybutynin, resulted in very little reduction in the B_<max> valules for (-)-[^3H] QNB binding in the submaxillary gland. In conclusion, the present study has shown that oxybutynin and propiverine, after oral administration, bind significantly to muscarinic receptors in tissues such as the bladder and that oxybutynin appears to exhibit long-term binding to muscarinic receptors in the salivary gland.[Experiment II] : Following the oral administration of Oxy, there was a significant increase in dissociation constant (K_d) for specific [N-methyl-^3H] scopolamine (NMS) binding in urinary bladder, submaxillary gland, heart and colon of rats compared with the value of control rats, and a concomitant reduction of maximal number of binding sites (B_<max>) only in submaxillary gland and heart. Such increase in K_d value in each tissue was seen at 1 and 3 hr after oral administration of Oxy, but not at 12 and 24 hr. In contrast, a significant reduction of B_<max> value in submaxillary gland and heart was maintained for at least 24 hr. Transdermal application of MM-801 for 2-48 hr caused a significant increase in K_d value for [^3H] NMS binding in bladder, submaxillary gland, heart and colon of rats, and there was little reduction of B_<max> value in each tissue. The increment of K_d value increased with the application time of MM-801, being maximal at 12 hr later. These data suggest that the transdermally administered Oxy (MM-801) binds significantly to the muscarinic receptor in urinary bladder of rats and the binding to the receptor in submaxillary gland is easily reversible by this TTS but not by the oral administration. The present study may provide a rationale for the usefulness of transdermal application of Oxy in the therapy of DI. Less