Although in vitro studies show that
muscarinic M(3) receptors primarily mediate the effects of
acetylcholine on gastrointestinal contractility, the
muscarinic receptor subtypes regulating gastrointestinal motor activity and transit in humans in vivo are unclear. We hypothesized that
muscarinic M(3)-specific but not nonspecific receptor antagonists would delay gastrointestinal and colonic transit in humans. In this parallel-group study, gastric emptying, small intestinal transit, and colonic transit were assessed by scintigraphy on days 4-6 in 72 healthy subjects (49 women) who received placebo (n = 16), the M(3) antagonist
darifenacin ER [7.5 mg (n = 20) or 15 mg daily (n = 17)], or the nonspecific antagonist
tolterodine [4 mg daily (n = 19)] for 6 days. Bowel habits were recorded by daily diaries. Both doses of
darifenacin substantially delayed [P < 0.01 vs. placebo (for both doses), P < 0.01 vs.
tolterodine (for 15 mg)] small intestinal transit, i.e., colonic filling at 6 h (placebo [59.6 +/- 6.4%, mean +/- SE], 7.5 mg ER [34.4 +/- 6.1%], 15 mg ER [20.4 +/- 6.3%)].
Darifenacin (15 mg) also delayed (P < 0.01 vs. placebo and
tolterodine) half-time for ascending colonic emptying [placebo (12.0 +/- 1.5 h), 7.5 mg (18.6 +/- 1.9 h), 15 mg (22.9 +/- 2.6 h)] and colonic transit (geometric center) at 24 [placebo (2.8 +/- 0.2), 7.5 mg (2.4 +/- 0.2), 15 mg (1.9 +/- 0.2)] but not 48 h.
Darifenacin did not affect gastric emptying and
tolterodine did not affect bowel habits or gastrointestinal transit. With
muscarinic antagonists used at clinically approved doses, these findings demonstrate that
muscarinic M(3) receptors regulate small intestinal and colonic transit in humans; colonic effects are more pronounced in the right than left colon. At doses that affect small and large intestinal transit, M(3) antagonists do not affect gastric emptying in humans. The efficacy of
darifenacin in
diarrhea-predominant
irritable bowel syndrome should be evaluated.