Chenodeoxycholate in females with irritable bowel syndrome-constipation: a pharmacodynamic and pharmacogenetic analysis.
OBJECTIVE
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.
Rao
Archana S
AS
Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Biomedical Statistics and Informatics, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
Wong
Banny S
BS
Camilleri
Michael
M
Odunsi-Shiyanbade
Suwebatu T
ST
McKinzie
Sanna
S
Ryks
Michael
M
Burton
Duane
D
Carlson
Paula
P
Lamsam
Jesse
J
Singh
Ravinder
R
Zinsmeister
Alan R
AR
D000284:Administration, Oral; D000328:Adult; D001647:Bile Acids and Salts / Q000096:biosynthesis; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002783:Cholestenones / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000235:genetics; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000235:genetics; D005500:Follow-Up Studies; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005772:Gastrointestinal Transit / Q000187:drug effects / Q000502:physiology*; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D013058:Mass Spectrometry; D008875:Middle Aged; D011110:Polymorphism, Genetic; D051499:Receptor, Fibroblast Growth Factor, Type 4 / Q000096:biosynthesis / Q000235:genetics; D012189:Retrospective Studies; D016896:Treatment Outcome
D001647:Bile Acids and Salts; D002783:Cholestenones; D003692:Delayed-Action Preparations; C117476:FGF19 protein, human; D005765:Gastrointestinal Agents; D002635:Chenodeoxycholic Acid; C002656:7 alpha-hydroxy-4-cholesten-3-one; D005346:Fibroblast Growth Factors; D004247:DNA; C496371:FGFR4 protein, human; D051499:Receptor, Fibroblast Growth Factor, Type 4