Pharmacokinetics of the opioid antagonist N-methylnaltrexone and evaluation of its effects on gastrointestinal tract function in horses treated or not treated with morphine

Objective-To determine the pharmacokinetics and effects of the morphine antagonist N-methylnaltrexone (MNTX) on gastrointestinal tract function in horses when administered alone and in combination with morphine. Animals-5 healthy adult horses. Procedures-Horses were treated with MNTX (1 mg/kg, IV), and serial blood samples were collected for determination of drug pharmacokinetics. For evaluation of effects on the gastrointestinal tract when administered alone, MNTX was administered at a dosage of 0.75 mg/kg, IV, twice daily for 4 days. For evaluation of effects when administered concurrently with morphine, MNTX (0.75 mg/kg, IV, q 12 hours) and morphine (0.5 mg/kg, IV, q 12 hours) were administered for 6 days. Gastrointestinal variables evaluated were defecation frequency, weight of feces produced, fecal moisture content, intestinal transit time, and borborygmus scores. Results-The time-concentration data for MNTX disposition best fit a 2-compartment model with a steady-state volume of distribution of 244.6 +/- 21.8 mL/kg, t(1/2) of 47.04 +/- 11.65 minutes, and clearance of 11.43 +/- 1.06 mL/min/kg. Adverse effects were not observed at doses <= 1 mg/kg. Administration of MNTX increased daily fecal weight. When administered concurrently with morphine, MNTX partially prevented the effects of morphine on the gastrointestinal tract by increasing defecation frequency, fecal weight, fecal moisture content, and borborygmus score, and by preventing increases in intestinal transit time. Conclusions and Clinical Relevance-Because MNTX does not cross the blood-brain barrier, administration of the drug should not alter the analgesic effects of opioids and may attenuate the adverse gastrointestinal effects associated with use of opioids in horses.