Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea.

Abstract

BACKGROUND:

Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS-D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO's effects on colonic motility. Our aims were: (i) to compare dose-related effects of DRO to placebo (PLA) on gut transit in IBS-D, and (ii) to examine influence of genetic variations in CB mechanisms on DRO’s transit effects.

METHODS:

Thirty-six IBS-D volunteers were randomized (double-blind, concealed allocation) to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model.

KEY RESULTS:

Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected.

CONCLUSIONS & INFERENCES:

Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut transit in IBS-D. There appears to be a treatment-by-genotype effect, whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS-D patients most likely to benefit from CB agonist therapy.

• Authors: B S Wong, M Camilleri, D Eckert, P Carlson, M Ryks, D Burton, A R Zinsmeister
• Journal: Neurogastroenterology and motility (Neurogastroenterol Motil) Vol. 24 Issue 4 Pg. 358-e169 (Apr 2012) ISSN: 1365-2982 [Electronic] England
• PMID: 22288893 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Blackwell Publishing Ltd.

Chemical References

• Analgesics, Non-Narcotic
• CNR1 protein, human
• Receptor, Cannabinoid, CB1
• Dronabinol
• Amidohydrolases
• fatty-acid amide hydrolase

Topics

• Amidohydrolases (genetics)
• Analgesics, Non-Narcotic (administration & dosage, pharmacokinetics)
• Diarrhea (drug therapy, etiology, genetics)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Dronabinol (administration & dosage, pharmacokinetics)
• Gastrointestinal Transit (drug effects, genetics)
• Genomics
• Genotype
• Humans
• Irritable Bowel Syndrome (complications, drug therapy, genetics)
• Polymorphism, Single Nucleotide
• Receptor, Cannabinoid, CB1 (genetics)