BACKGROUND & AIMS:Sodium chenodeoxycholate (CDC) accelerates colonic transit in health. Our aim was to examine pharmacodynamics (colonic transit, bowel function) and pharmacogenetics of CDC in constipation-predominant irritable bowel syndrome (IBS-C). METHODS: In a double-blind placebo-controlled study, 36 female patients with IBS-C were randomized to treatment with delayed-release oral formulations of placebo, 500 mg CDC, or 1000 mg CDC for 4 days. We assessed gastrointestinal and colonic transit, stool characteristics, and associations of transit with fasting serum7αC4 (surrogate of bile acid synthesis) and FGF19 (negative regulator of bile acid synthesis) levels. Candidate genetic polymorphisms involved in regulation of bile acid synthesis were analyzed in the 36 patients with IBS-C and 57 healthy volunteers to assess genetic influence on effects of CDC on transit. RESULTS:Overall colonic transit and ascending colon emptying (AC t(½)) were significantly accelerated in the CDC group compared with placebo (P = .005 and P = .028, respectively). Looser stool consistency (P = .003), increased stool frequency (P = .018), and greater ease of passage (P = .024) were noted with CDC compared with placebo. The most common side effect was lower abdominal cramping/pain (P = .01). Fasting serum7αC4 (but not FGF19) was positively associated with colonic transit (r(s) = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t(½) in response to CDC (uncorrected P = .015); αKlothoβ variant showed a gene-by-treatment interaction based on patient subgroup (uncorrected P = .0088). CONCLUSIONS:CDC accelerates colonic transit and improves bowel function in female patients with IBS-C. The rate of bile acid synthesis influences colonic transit. Genetic variation in negative feedback inhibition of bile acid synthesis may affect CDC-mediated acceleration of colonic transit.
RCT Entities:
BACKGROUND & AIMS:Sodium chenodeoxycholate (CDC) accelerates colonic transit in health. Our aim was to examine pharmacodynamics (colonic transit, bowel function) and pharmacogenetics of CDC in constipation-predominant irritable bowel syndrome (IBS-C). METHODS: In a double-blind placebo-controlled study, 36 female patients with IBS-C were randomized to treatment with delayed-release oral formulations of placebo, 500 mg CDC, or 1000 mg CDC for 4 days. We assessed gastrointestinal and colonic transit, stool characteristics, and associations of transit with fasting serum 7αC4 (surrogate of bile acid synthesis) and FGF19 (negative regulator of bile acid synthesis) levels. Candidate genetic polymorphisms involved in regulation of bile acid synthesis were analyzed in the 36 patients with IBS-C and 57 healthy volunteers to assess genetic influence on effects of CDC on transit. RESULTS: Overall colonic transit and ascending colon emptying (AC t(½)) were significantly accelerated in the CDC group compared with placebo (P = .005 and P = .028, respectively). Looser stool consistency (P = .003), increased stool frequency (P = .018), and greater ease of passage (P = .024) were noted with CDC compared with placebo. The most common side effect was lower abdominal cramping/pain (P = .01). Fasting serum 7αC4 (but not FGF19) was positively associated with colonic transit (r(s) = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t(½) in response to CDC (uncorrected P = .015); αKlothoβ variant showed a gene-by-treatment interaction based on patient subgroup (uncorrected P = .0088). CONCLUSIONS:CDC accelerates colonic transit and improves bowel function in female patients with IBS-C. The rate of bile acid synthesis influences colonic transit. Genetic variation in negative feedback inhibition of bile acid synthesis may affect CDC-mediated acceleration of colonic transit.
Authors: Alan F Hofmann; Vera Loening-Baucke; Joel E Lavine; Lee R Hagey; Joseph H Steinbach; Christine A Packard; Terrance L Griffin; Dale A Chatfield Journal: J Pediatr Gastroenterol Nutr Date: 2008-11 Impact factor: 2.839
Authors: H Buchwald; R L Varco; J R Boen; S E Williams; B J Hansen; C T Campos; G S Campbell; M B Pearce; A E Yellin; W A Edmiston; R D Smink; H S Sawin Journal: Arch Intern Med Date: 1998-06-08
Authors: Viola Andresen; Michael Camilleri; Irene A Busciglio; April Grudell; Duane Burton; Sanna McKinzie; Amy Foxx-Orenstein; Caroline B Kurtz; Vineeta Sharma; Jeffrey M Johnston; Mark G Currie; Alan R Zinsmeister Journal: Gastroenterology Date: 2007-07-03 Impact factor: 22.682
Authors: Julian R F Walters; Ali M Tasleem; Omer S Omer; W Gordon Brydon; Tracy Dew; Carel W le Roux Journal: Clin Gastroenterol Hepatol Date: 2009-05-06 Impact factor: 11.382
Authors: M Camilleri; A Nadeau; W J Tremaine; J Lamsam; D Burton; S Odunsi; S Sweetser; R Singh Journal: Neurogastroenterol Motil Date: 2009-03-13 Impact factor: 3.598
Authors: Stefano Ginanni Corradini; Flaminia Ferri; Michela Mordenti; Luigi Iuliano; Maria Siciliano; Maria Antonella Burza; Bruno Sordi; Barbara Caciotti; Maria Pacini; Edoardo Poli; Adriano De Santis; Aldo Roda; Carolina Colliva; Patrizia Simoni; Adolfo Francesco Attili Journal: World J Gastroenterol Date: 2012-03-07 Impact factor: 5.742
Authors: Banny S Wong; Michael Camilleri; Paula Carlson; Sanna McKinzie; Irene Busciglio; Olga Bondar; Roy B Dyer; Jesse Lamsam; Alan R Zinsmeister Journal: Clin Gastroenterol Hepatol Date: 2012-05-18 Impact factor: 11.382
Authors: Michael Camilleri; Eric W Klee; Andrea Shin; Paula Carlson; Ying Li; Madhusudan Grover; Alan R Zinsmeister Journal: Am J Physiol Gastrointest Liver Physiol Date: 2013-11-07 Impact factor: 4.052
Authors: M Camilleri; M I Vazquez-Roque; P Carlson; D Burton; B S Wong; A R Zinsmeister Journal: Neurogastroenterol Motil Date: 2011-08-24 Impact factor: 3.598