Effect of CCK-1 antagonist, dexloxiglumide, in female patients with irritable bowel syndrome: a pharmacodynamic and pharmacogenomic study.
BACKGROUND
Cholecystokinin (CCK) is involved in gastrointestinal motor response to meals. The potential role of CCK receptor antagonists in functional gastrointestinal disorders is unclear.


OBJECTIVE
To evaluate the effects of dexloxiglumide, a CCK-1 receptor antagonist, on gastrointestinal transit (GIT) and symptoms in patients with constipation-predominant IBS (C-IBS); and to explore the influence of CCK-1 receptor polymorphisms on gut transit and the pharmacodynamic response to therapy.


METHODS
A total of 36 patients with C-IBS and normal to slow baseline colonic transit (CT) were randomized (double-blind, parallel design) to 7 days of dexloxiglumide 200 mg or placebo t.i.d. Daily bowel habits diaries and weekly relief of IBS symptoms were recorded. At the end of treatment, GIT and CT were measured. Peripheral blood DNA was examined for polymorphisms in genes controlling CCK: four related to CCK-1, one to the CCK gene promoter, and one related to CCK-2. The distributions of allelic variants and association with gastric emptying in response to dexloxiglumide and placebo were assessed.


RESULTS
Dexloxiglumide was associated with accelerated gastric emptying t(1/2) (p= 0.004), and slower ascending colon emptying t(1/2) (p < 0.01), with no significant effect on overall CT or satisfactory relief of IBS. There was an association between CCK 779T > C polymorphism and slower rate of gastric emptying (p= 0.04).


CONCLUSIONS
Dexloxiglumide accelerates gastric emptying and delays proximal but not overall CT in patients with C-IBS. Dexloxiglumide does not accelerate transit in C-IBS. The role of CCK-1 gene polymorphisms in delaying gastric emptying and in determining response to therapy deserves further study.
Cremonini
Filippo
F
Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) Program, Gastroenterology Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota.
Camilleri
Michael
M
McKinzie
Sanna
S
Carlson
Paula
P
Camilleri
Christopher E
CE
Burton
Duane
D
Thomforde
George
G
Urrutia
Raul
R
Zinsmeister
Alan R
AR
D000328:Adult; D003248:Constipation / Q000188:drug therapy; D004311:Double-Blind Method; D005260:Female; D005746:Gastric Emptying; D005772:Gastrointestinal Transit / Q000187:drug effects; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D010349:Patient Compliance; D010421:Pentanoic Acids / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors* / Q000235:genetics
D010421:Pentanoic Acids; D011949:Receptors, Cholecystokinin; C103490:dexloxiglumide