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Chenodeoxycholate in Females With Irritable Bowel Syndrome-Constipation: A Pharmacodynamic and Pharmacogenetic Analysis.

Gastroenterology. 2010 Aug 4;

Authors: Rao AS, Wong BS, Camilleri M, Odunsi-Shiyanbade ST, McKinzie S, Ryks M, Burton D, Carlson P, Lamsam J, Singh R, Zinsmeister AR

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 IBS-C patients were randomized to delayed-release formulations of oral placebo, 500mg or 1000mg CDC for 4 days. We assessed GI and colonic transit, stool characteristics, and associations of transit with fasting serum 7alphaC4 (surrogate of bile acid synthesis) and FGF19 (negative regulator of bile acid synthesis). Candidate genetic polymorphisms involved in regulation of bile acid synthesis were analyzed in these 36 IBS-C patients and 57 healthy volunteers to assess genetic influence on effects of CDC on transit. RESULTS:: Overall colonic transit and ascending colon emptying (AC t(1/2)) were significantly accelerated in the CDC group compared with placebo (p=0.005 and p=0.028, respectively). Looser stool consistency (p=0.003), increased stool frequency (p=0.018) and greater ease of passage (p=0.024) were noted with CDC compared with placebo. The most common side effect was lower abdominal cramping/pain (p=0.01). Fasting serum 7alphaC4 (but not FGF19) was positively associated with colonic transit (r(s)=0.749, p=0.003, placebo group). Genetic variation in FGFR4 was associated with AC t(1/2) in response to CDC (uncorrected p=0.015); Klothobeta demonstrated a gene-by-treatment interaction based on patient subgroup (uncorrected p=0.0088). CONCLUSIONS:: CDC accelerates colonic transit and improves bowel function in female IBS-C patients. 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.

PMID: 20691689 [PubMed - as supplied by publisher]

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