Chenodeoxycholate in females with irritable bowel syndrome-constipation

A pharmacodynamic and pharmacogenetic analysis

Archana S. Rao, Banny S. Wong, Michael Camilleri, Suwebatu T. Odunsishiyanbade, Sanna McKinzie, Michael Ryks, Duane Burton, Paula Carlson, Jesse Lamsam, Ravinder Jit Singh, Alan R. Zinsmeister

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

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 t1/2) 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 (rs = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t1/2 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.

Original languageEnglish (US)
JournalGastroenterology
Volume139
Issue number5
DOIs
StatePublished - Nov 2010

Fingerprint

Chenodeoxycholic Acid
Irritable Bowel Syndrome
Constipation
Bile Acids and Salts
Placebos
Fasting
Pharmacogenomic Testing
Gastrointestinal Transit
Ascending Colon
Pharmacogenetics
Genetic Polymorphisms
Serum
Abdominal Pain
Healthy Volunteers

Keywords

  • 7αC4
  • Bile Acid
  • FGF19
  • FGFR4

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Chenodeoxycholate in females with irritable bowel syndrome-constipation : A pharmacodynamic and pharmacogenetic analysis. / Rao, Archana S.; Wong, Banny S.; Camilleri, Michael; Odunsishiyanbade, Suwebatu T.; McKinzie, Sanna; Ryks, Michael; Burton, Duane; Carlson, Paula; Lamsam, Jesse; Singh, Ravinder Jit; Zinsmeister, Alan R.

In: Gastroenterology, Vol. 139, No. 5, 11.2010.

Research output: Contribution to journalArticle

Rao, AS, Wong, BS, Camilleri, M, Odunsishiyanbade, ST, McKinzie, S, Ryks, M, Burton, D, Carlson, P, Lamsam, J, Singh, RJ & Zinsmeister, AR 2010, 'Chenodeoxycholate in females with irritable bowel syndrome-constipation: A pharmacodynamic and pharmacogenetic analysis', Gastroenterology, vol. 139, no. 5. https://doi.org/10.1053/j.gastro.2010.07.052
Rao, Archana S. ; Wong, Banny S. ; Camilleri, Michael ; Odunsishiyanbade, Suwebatu T. ; McKinzie, Sanna ; Ryks, Michael ; Burton, Duane ; Carlson, Paula ; Lamsam, Jesse ; Singh, Ravinder Jit ; Zinsmeister, Alan R. / Chenodeoxycholate in females with irritable bowel syndrome-constipation : A pharmacodynamic and pharmacogenetic analysis. In: Gastroenterology. 2010 ; Vol. 139, No. 5.
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abstract = "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 t1/2) 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 (rs = 0.749, P = .003, placebo group). Genetic variation in FGFR4 was associated with AC t1/2 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.",
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AU - Odunsishiyanbade, Suwebatu T.

AU - McKinzie, Sanna

AU - Ryks, Michael

AU - Burton, Duane

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