Aims of Study.
Antimuscarinic agent, oxybutynin, is widely used for the treatment of detrusor instability (DI) or detrusor hyperreflexia which is characterized by symptoms of increased frequency of micturition and urge urinary incontinence [1]. However, the use of this drug is often limited by systemic side effects such as dry mouth known to occur frequently with orally administered oxybutynin. The incidence of dry mouth is expected to be lower with transdermal application of oxybutynin than oral administration. The transdermal therapeutic system (TTS) of oxybutynin (MM-801) has been currently developed and its usefulness is now under investigation. The therapeutic effect and dry mouth by oxybutynin in patients with DI are mainly based on the blockade of muscarinic receptors in the bladder and salivary gland, respectively. The analysis of drug-receptor binding in different tissues in relation to the pharmacokinetics is very useful in characterizing pharmacological specificity (potency, duration of action and tissue selectivity) of the drug [2]. To clarify the usefulness of transdermally administered oxybutynin in the therapy of DI, therefore, we characterized muscarinic receptor binding in rat tissues after the transdermal application of MM-801 in comparison with that after the oral administration of oxybutynin.

Methods.
At 1 to 48 hr after the oral and transdermal administration of oxybutynin, rats were sacrificed by exsanguination from the descending aorta, and the bladder, submaxillary gland, heart and colon were dissected. The mucarinic receptor in each tissue was measured by a radioreceptor binding assay with [N-methyl-3H]scopolamine (NMS) as a radioligand, and binding constants of apparent dissociation constant (Kd) and maximal number of binding sites (Bmax) for [3H]NMS were estimated by Scatchard analysis [3,4]. The concentration of oxybutynin and its active metabolite, N-desethyloxybutynin (DEOB) in the plasma was also measured.

Results.
Following the oral administration of oxybutynin (127 mmol/kg), there was a significant increase in Kd value for specific [3H]NMS binding in the bladder, submaxillary gland, heart and colon of rats compared with the value of control rats, and a concomitant reduction of Bmax value only in the submaxillary gland and heart. Such increase in Kd value in each tissue was seen at 1 and 3 hr after the oral administration of oxybutynin, but not at 12 and 24 hr. In contrast, a significant reduction of Bmax value in the submaxillary gland and heart was maintained for at least 24 hr. The plasma concentration of oxybutynin and DEOB was maximal at 1 hr after the oral administration and it was extremely low at 12 and 24 hr later. The transdermal application of MM-801 (one patch containing 33.6 mmol oxybutynin base/body) for 2, 4, 12, 24 and 48 hr brought about a significant increase in Kd value for specific [3H]NMS binding in the bladder, submaxillary gland, heart and colon of rats, and there was little reduction of Bmax value in each tissue. The increment of Kd value increased with the application time of MM-801, being maximal at 12 hr later. The plasma concentration of oxybutynin increased with the application time, and the maximal level was seen at 12 hr and maintained until the application time of 48 hr. DEOB was not detected in the plasma of MM-801-administered rats. In rats at 8 hr after the removal of MM-801 following the 48 hr-application, the increase in Kd value for [3H]NMS binding in each tissue was no longer seen and the plasma concentration of oxybutynin was markedly low.

Conclusions.
These data suggest that the transdermally administered oxybutynin (MM-801) binds significantly to the muscarinic receptor in the bladder of rats and the binding to the receptor in the submaxillary gland is easily reversible by this TTS but not by the oral administration. Thus, the present study may provide a rationale for the usefulness of tansdermal application of oxybutynin in the therapy of DI.

References.
[1] Drugs & Aging 6: 243-262 (1995)
[2] Current Topics in Pharmacology (Research Trends) 4: 239-250 (1998)
[3] J.Pharmacol.Exp.Ther. 255: 1148-1157 (1990)
[4] J.Pharmacol.Exp.Ther. 215: 176-185 (1980)