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- Title
Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea.
- Authors
Wong, B. S.; Camilleri, M.; Eckert, D.; Carlson, P.; Ryks, M.; Burton, D.; Zinsmeister, A. R.
- 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.
- Subjects
IRRITABLE colon; DIARRHEA; MOTILITY of the colon; PLACEBOS; PHARMACOGENOMICS
- Publication
Neurogastroenterology & Motility, 2012, Vol 24, Issue 4, p358
- ISSN
1350-1925
- Publication type
Article
- DOI
10.1111/j.1365-2982.2011.01874.x