Demonstration of bladder selective muscarinic receptor binding by intravesical oxybutynin to treat overactive bladder.
OBJECTIVE
The current study was done to elucidate the in vivo mechanism of action of intravesical instillation of oxybutynin to treat overactive bladder.


METHODS
In rats receiving oral and intravesical oxybutynin we measured muscarinic receptors in the bladder and other tissues by radioligand binding assay using [3H]NMS ([N-methyl-3H] scopolamine methyl chloride) with the simultaneous measurement of plasma concentrations of oxybutynin and its active metabolite N-desethyl-oxybutynin. Pilocarpine induced salivary secretion was also measured.


RESULTS
Following oral administration of oxybutynin there was a significant increase in the apparent dissociation constant (Kd) for specific [3H]NMS binding in the bladder, submaxillary gland, heart and colon of rats at 1 and 3 hours with a consistent decrease in the maximal number of binding sites (Bmax) in the submaxillary gland. Furthermore, a marked and prolonged decrease in pilocarpine induced salivary secretion in rats was observed by oral oxybutynin. In contrast, intravesical instillation of oxybutynin produced a significant increase in Kd for specific [3H]NMS binding in the bladder of rats at 0.5 to 4 hours later and also in the submaxillary gland only at 0.5 hours later. The enhancement in Kd was much larger and longer lasting in the bladder than in the submaxillary gland. Moreover, intravesical oxybutynin had little muscarinic receptor binding activity in the heart and colon, and little significant suppression of pilocarpine induced salivation in rats. The plasma concentrations of oxybutynin and N-desethyl-oxybutynin were much higher in rats receiving oxybutynin orally than intravesically.


CONCLUSIONS
Intravesical oxybutynin in rats may cause selective binding of bladder muscarinic receptors via a direct local effect, while oral oxybutynin may exert predominant binding of salivary gland receptors.
Oki
Tomomi
T
Department of Biopharmaceutical Sciences and COE Program in the 21st Century, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
Kimura
Ryohei
R
Saito
Motoaki
M
Miyagawa
Ikuo
I
Yamada
Shizuo
S
D000283:Administration, Intravesical; D000818:Animals; D008297:Male; D008333:Mandelic Acids / Q000378:metabolism* / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D001743:Urinary Bladder / Q000378:metabolism*; D001745:Urinary Bladder Diseases / Q000188:drug therapy*
D008333:Mandelic Acids; D011976:Receptors, Muscarinic; C005419:oxybutynin