Differential effects of selective and non-selective muscarinic antagonists on gastrointestinal transit and bowel function in healthy women


Address for Correspondence
Adil E. Bharucha, MD, Clinical and Enteric Neuroscience Translational and Epidemiological Research Program (C.E.N.T.E.R.), Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA.
Tel: 507-538-5854; fax: 507-538-5820;
e-mail: bharucha.adil@mayo.edu


Background  The gastrointestinal effects of antimuscarinic drugs used to treat overactive bladder may be related to the selectivity of these agents for M3-muscarinic receptor subtypes. We compared the effects of non-selective (fesoterodine) and M3-selective (solifenacin) antimuscarinics on gastrointestinal transit in healthy women.

Methods  Gastric emptying (GE), small-intestinal transit (colonic filling at 6 h), colonic transit [geometric center at 24 h (GC24; primary endpoint) and 48 h (GC48)], and bowel habits were assessed by scintigraphy and bowel diaries before and after randomization to fesoterodine 8 mg, solifenacin 10 mg, or placebo (2 : 2 : 1) for 14 days. An interim analysis to finalize sample size was conducted.

Key Results  After 60 subjects [placebo (n = 12), fesoterodine (n = 25), solifenacin (n = 23)] completed the study, the study was terminated due to a prespecified criterion (sample size ≥452.5 needed to provide ≥80% power to demonstrate superiority of fesoterodine over solifenacin in GC24). Compared with baseline, (i) placebo delayed small-intestinal, but not colonic, transit, (ii) fesoterodine significantly increased GE t1/2vs placebo (17.0 min; P = 0.027), and (iii) fesoterodine and solifenacin delayed small-intestinal (−36.8% and −21.8%, respectively, < 0.001 vs placebo) and colonic transit (GC24: −0.44 and −0.49, respectively, < 0.05 vs placebo; GC48: −0.25 and −0.65, respectively, > 0.05 vs placebo). Solifenacin increased stool hardness from baseline (P = 0.010 for difference vs fesoterodine); stool frequency was comparable.

Conclusions & Inferences  In healthy women, fesoterodine had greater effects on small-intestinal transit and solifenacin had greater effects on colonic transit; the latter finding may explain why solifenacin, but not fesoterodine, increased stool hardness. (ClinicalTrials.gov ID: NCT00892034).