Effect of a chloride channel activator, lubiprostone, on colonic sensory and motor functions in healthy subjects

Abstract

Lubiprostone, a bicyclic fatty acid chloride channel activator, is efficacious in treatment of chronic constipation and constipation-predominant irritable bowel syndrome. The study aim was to compare effects of lubiprostone and placebo on colonic sensory and motor functions in humans. In double-blind, randomized fashion, 60 healthy adults received three oral doses of placebo or 24 microg lubiprostone per day in a parallel-group, placebo-controlled trial. A barostat-manometry tube was placed in the left colon by flexible sigmoidoscopy and fluoroscopy. We measured treatment effects on colonic sensation and motility with validated methods, with the following end points: colonic compliance, fasting and postprandial tone and motility indexes, pain thresholds, and sensory ratings to distensions. Among participants receiving lubiprostone or placebo, 26 of 30 and 28 of 30, respectively, completed the study. There were no overall effects of lubiprostone on compliance, fasting tone, motility indexes, or sensation. However, there was a treatment-by-sex interaction effect for compliance (P = 0.02), with lubiprostone inducing decreased fasting compliance in women (P = 0.06) and an overall decreased colonic tone contraction after a standard meal relative to fasting tone (P = 0.014), with greater effect in women (P < 0.01). Numerical differences of first sensation and pain thresholds (P = 0.11 in women) in the two groups were not significant. We concluded that oral lubiprostone 24 microg does not increase colonic motor function. The findings of decreased colonic compliance and decreased postprandial colonic tone in women suggest that motor effects are unlikely to cause accelerated colonic transit with lubiprostone, although they may facilitate laxation. Effects of lubiprostone on sensitivity deserve further study.

Fig. 1.

Effects of lubiprostone and placebo on colonic compliance: overall (male and female) data.

Fig. 2.

Effects of lubiprostone and placebo on colonic fasting tone, postprandial (PP) tone over 60 min, and relative change in colonic tone during first 30 min after meal compared with fasting. Results obtained in all participants. Note the significantly lower colonic tone contractile response to standard meal ingestion relative to the fasting colonic tone. There is a trend to a higher fasting colonic tone (lower volume) with lubiprostone treatment. Relative change in tone is calculated as 100 × log_e (average baseline volume in first 30 min postprandially/average baseline volume in fasting 30 min premeal).

Fig. 3.

Effects of lubiprostone and placebo on colonic compliance in women only, showing decreased colonic compliance (higher Pr 1/2) in women.

Fig. 4.

Effects of lubiprostone and placebo on colonic compliance, fasting tone, postprandial tone over 60 min, and relative change in colonic tone during first 30 min after meal compared with fasting. Results obtained only in women show a borderline significant effect on compliance in women (P = 0.06) and a significant effect on the relative change in postprandial tone (P < 0.01).

Fig. 5.

Effects of lubiprostone and placebo on sensory thresholds. Note that, although the curves for first sensation and pain are shifted to the right with lubiprostone (by an average of 4 mmHg for the pressure when 50% participants declared those sensations), this reduction in pain sensation with lubiprostone was not statistically significant.

Fig. 6.

Effects of lubiprostone and placebo on sensory ratings. Data are shown pre- and posttreatment and show the absence of any significant change in sensory ratings with treatment. VAS, visual analog scale; BOP, baseline operating pressure.