Pharmacological characterization of a novel investigational antimuscarinic drug, fesoterodine, in vitro and in vivo.
OBJECTIVE
To investigate the primary pharmacology of fesoterodine (a novel antimuscarinic drug developed for treating overactive bladder) and SPM 7605 (its active metabolite, considered to be the main pharmacologically active principle of fesoterodine in man) against human muscarinic receptor subtypes, and to investigate in vitro and in vivo functional activity of these agents on the rat bladder compared with existing standard agents.


METHODS
The displacement of radioligand binding by fesoterodine, SPM 7605 and standard agents in membrane preparations of Chinese hamster ovary (CHO) cells expressing the different human muscarinic receptors (M1-M5) was characterized. Agonistic and antagonistic activities were studied using different CHO cell lines stably expressing the human recombinant muscarinic receptor subtypes. The effects of fesoterodine and SPM 7605 on isolated bladder strips contracted by carbachol or electrical field stimulation (EFS) were investigated. In vivo the effects of fesoterodine and SPM 7605 on micturition variables were assessed using continuous cystometry in conscious female Sprague-Dawley rats, and compared to those of oxybutynin and atropine.


RESULTS
In vitro SPM 7605 potently inhibited radioligand binding at all five human muscarinic receptor subtypes with equal affinity across all five. Fesoterodine had a similar balanced selectivity profile but was less potent than SPM 7605. Both substances were competitive antagonists of cholinergic agonist-stimulated responses in human M1-M5 cell lines and had a similar potency and selectivity profile to the radioligand-binding studies. In rat bladder strips, fesoterodine and SPM 7605 caused a rightward shift of the concentration-response curve for carbachol with no depression of the maximum, and concentration-dependently reduced contractions induced by EFS. The potency of both drugs was similar to that of atropine and oxybutynin. In the presence of the esterase inhibitor neostigmine, the concentration-response curve of fesoterodine was shifted to the right, suggesting that part of the activity was caused by metabolism to SPM 7605 by tissue enzymes. In vivo, low doses (0.01 mg/kg) of fesoterodine and SPM 7605 reduced micturition pressure and increased intercontraction intervals and bladder capacity, but did not affect residual volume.


CONCLUSIONS
Fesoterodine and its active metabolite, SPM 7605, are nonsubtype selective, competitive antagonists of human muscarinic receptors, but SPM 7605 has greater potency than the parent compound. Pharmacodynamic studies in the rat bladder in vitro confirm the competitive muscarinic antagonist profile of these agents in a native tissue preparation, and in vivo studies in the rat showed effects on bladder function consistent with a muscarinic antagonist profile.
Ney
Peter
P
Department of Pharmacology/Toxicology, Schwarz BioSciences GmbH, Monheim, Germany.
Pandita
Raj Kumar
RK
Newgreen
Donald T
DT
Breidenbach
Alexander
A
Stöhr
Thomas
T
Andersson
Karl-Erik
KE
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*; D053201:Urinary Bladder, Overactive / Q000188:drug therapy*
D001559:Benzhydryl Compounds; D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; C526675:fesoterodine