Comparative evaluation of central muscarinic receptor binding activity by oxybutynin, tolterodine and darifenacin used to treat overactive bladder.
OBJECTIVE
We characterized muscarinic receptor binding in the mouse cerebral cortex after oral administration of anticholinergic agents used to treat overactive bladder.


METHODS
Muscarinic receptors in the mouse cerebral cortex and bladder after oral administration of anticholinergic agents were measured using [(3)H]N-methylscopolamine.


RESULTS
In vitro binding affinities of tolterodine and its metabolite 5-hydroxymethyl metabolite in the mouse cerebral cortex and bladder were considerably greater than those of oxybutynin and darifenacin. Also, muscarinic receptor binding affinity of oxybutynin and its metabolite N-desethyl-oxybutynin in the cerebral cortex compared with that in the bladder was 2 to 3 times higher, whereas that of tolterodine and 5-hydroxymethyl metabolite was approximately 2 times lower. Oral administration of oxybutynin (76.1 micromol/kg), tolterodine (6.31 micromol/kg) and darifenacin (59.1 micromol/kg) showed binding activity that was approximately equal to that of bladder muscarinic receptors. Oral administration of oxybutynin (76.1 micromol/kg) showed significant binding of cerebral cortical muscarinic receptors in mice, as indicated by about a 2-fold increase in K(d) values for specific [(3)H]N-methylscopolamine binding 0.5 and 2 hours later. On the other hand, tolterodine and darifenacin given at oral doses that would exert a similar extent of bladder receptor binding activity as oxybutynin showed only a low level of binding activity of central muscarinic receptors in mice.


CONCLUSIONS
Significant binding of brain muscarinic receptors in mice was observed by the oral administration of oxybutynin but not tolterodine and darifenacin.
Oki
Tomomi
T
Department of Pharmacokinetics and Pharmacodynamics, University of Shizuoka, Suruga-ku, Shizuoka, Japan.
Kageyama
Aiko
A
Takagi
Yukiko
Y
Uchida
Shinya
S
Yamada
Shizuo
S
D000818:Animals; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics*; D001572:Benzofurans / Q000493:pharmacokinetics*; D002540:Cerebral Cortex / Q000378:metabolism*; D003408:Cresols / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D008297:Male; D008333:Mandelic Acids / Q000493:pharmacokinetics*; D051379:Mice; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics*; D010665:Phenylpropanolamine / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000493:pharmacokinetics*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000378:metabolism*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
D001559:Benzhydryl Compounds; D001572:Benzofurans; D003408:Cresols; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C101207:darifenacin; C005419:oxybutynin