OBJECTIVES:

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.

INTRODUCTION

Chronic treatment of gallstones and cholestatic liver diseases with bile acids (BAs) consistently induces diarrhea (1). Disrupted enterohepatic circulation from ileal disease (eg, Crohn's disease, surgical resection, or radiation ileitis) with malabsorption and spillage of BA into the colon, results in chronic loose stools (2). This change in stool consistency results in part from colonic fluid and electrolyte secretion, as observed with colonic infusion of di-α-hydroxy BAs into mammalian and human colon (3, 4). The mechanisms involved in promoting colonic secretion include intracellular activation of adenylate cyclase (5), increased mucosal permeability (6, 7), and inhibition of apical Cl−/OH− exchange (8). BAs also induce propulsive contractions in the mammalian and human colon (9, 10), as may occur in patients with BA malabsorption. Patients with gallstones treated with chenodeoxycholic acid developed diarrhea (11). We have previously observed acceleration of colonic transit in healthy subjects and female patients with irritable bowel syndrome with constipation (IBS-C) by delivery of 500–1,000 mg sodium chenodeoxycholic acid to the ileocolonic region in a delayed-release capsule (12).