title: Effects of A3309, an ileal bile acid transporter inhibitor, on colonic transit and symptoms in females with functional constipation.
abstract: OBJECTIVE
  Delivery of bile acid (BA) to the colon stimulates propulsive motility and fluid secretion. The objective of this study was to examine gastrointestinal (GI) transit effects of A3309, a small molecule inhibitor of the ileal BA transporter, in patients with functional constipation (FC).
  
  
  METHODS
  In a double-blind, placebo-controlled study of 36 female FC patients randomized to placebo, 15 mg A3309, or 20 mg A3309 administered orally once daily for 14 consecutive days, we assessed GI and colonic transit, stool characteristics, symptoms of constipation, fasting serum C4 (7α-hydroxy-4-cholesten-3-one) (surrogate of BA synthesis and malabsorption), and fasting serum total and low-density lipoprotein (LDL) cholesterol (surrogates of inhibition of BA absorption). Following the intention-to-treat paradigm, we used analysis of covariance to assess the overall treatment effects and Dunnett's test for pairwise comparisons.
  
  
  RESULTS
  Overall colonic transit (geometric center at 24 h) was significantly accelerated with 20 mg A3309 compared with placebo (overall effect, P=0.059; A3309 15 mg, P=0.18; and A3309 20 mg, P=0.04). Colonic transit at 48 h was significantly accelerated with both A3309 dosages (overall effect, P<0.001; A3309 15 mg, P=0.002; and A3309 20 mg, P<0.001). Significantly looser stool consistency was noted with both A3309 dosages compared with placebo (P<0.005). Significant effects of A3309 on constipation rating, ease of stool passage, and reduction of straining were also detected. The most common side effect was lower abdominal cramping/pain. A3309 treatment significantly and reversibly increased fasting C4 (A3309 15 mg, P=0.05; A3309 20 mg, P<0.01) but did not affect fasting total and LDL cholesterol.
  
  
  CONCLUSIONS
  A3309 accelerates colonic transit and loosens stool consistency in FC patients.
authors.affiliation: Clinical Enteric Neuroscience Translational and Epidemiological Research, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Banny S
authors.initials: BS
authors.lastname: Wong
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.forename: Sanna
authors.initials: S
authors.lastname: McKinzie
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.forename: Hans
authors.initials: H
authors.lastname: Graffner
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002783:Cholestenones / Q000097:blood; D003085:Colic / Q000139:chemically induced; D003106:Colon / Q000187:drug effects / Q000503:physiopathology*; D003248:Constipation / Q000188:drug therapy* / Q000503:physiopathology; D003967:Diarrhea / Q000139:chemically induced; D004311:Double-Blind Method; D005243:Feces; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005772:Gastrointestinal Transit / Q000187:drug effects*; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D029363:Organic Anion Transporters, Sodium-Dependent / Q000037:antagonists & inhibitors*; D027981:Symporters / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
chemical_list: D002352:Carrier Proteins; D002783:Cholestenones; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter; C002656:7 alpha-hydroxy-4-cholesten-3-one