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Effects of enteric‐coated methylnaltrexone in preventing opioid‐induced delay in oral‐cecal transit time
Author(s) -
Yuan ChunSu,
Foss Joseph F.,
O'Connor Michael,
Karrison Theodore,
Osinski Joachim,
Roizen Michael F.,
Moss Jonathan
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.105037
Subject(s) - medicine , lactulose , morphine , placebo , enteric coated , oral administration , opioid , pharmacology , anesthesia , receptor , alternative medicine , pathology
Background Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine‐induced delay in gastrointestinal transit time. Methods This trial consisted of two studies: a pilot study and a controlled study. The lactulose hydrogen breath test was used to measure the oral‐cecal transit time. Results In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric‐coated methylnaltrexone effectively reversed the effects of morphine, producing transit times shorter than baseline levels. Subsequently, in the controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the lower dose (3.2 mg/kg) of enteric‐coated methylnaltrexone completely prevented the morphine‐induced change in oral‐cecal transit time in all nine subjects. Morphine significantly increased oral‐cecal transit time from baseline level of 96.7 ± 54.1 minutes (mean ± SD) to 155.0 ± 53.6 minutes ( P = .014). After enteric‐coated methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 ± 56.0 minutes; P = .55 compared with placebo). Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric‐coated methylnaltrexone were substantially lower compared with those after 6.4 mg/kg of the uncoated formulation. Conclusion Our results suggest that there is a prevailing direct and local luminal effect of enteric‐coated methylnaltrexone and that the enteric‐coated formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation. (Clin Pharmacol Ther 2000;67:398‐404.) Clinical Pharmacology & Therapeutics (2000) 67 , 398–404; doi: 10.1067/mcp.2000.105037