title: Comparison of selective M3 and nonselective muscarinic receptor antagonists on gastrointestinal transit and bowel habits in humans.
abstract: 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.
authors.affiliation: Clinical and Enteric Neuroscience Translational and Epidemiological Research Program (C.E.N.T.E.R.) Mayo Clinic and Mayo Foundation, 200 First St. S.W., Rochester, MN 55905, USA. bharucha.adil@mayo.edu
authors.forename: Adil E
authors.initials: AE
authors.lastname: Bharucha
authors.forename: Karthik
authors.initials: K
authors.lastname: Ravi
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000328:Adult; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001572:Benzofurans / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000378:metabolism; D003408:Cresols / Q000494:pharmacology*; D003672:Defecation / Q000187:drug effects*; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010665:Phenylpropanolamine / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D000068737:Tolterodine Tartrate; D055815:Young Adult
chemical_list: D001559:Benzhydryl Compounds; D001572:Benzofurans; D003408:Cresols; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D043587:Receptor, Muscarinic M3; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C101207:darifenacin
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