Variations in demethylation of N-methylnaltrexone in mice, rats, dogs, and humans

1. Rats and mice have a greater capacity than dogs or humans to N-demethylate the quaternary ammonium compound, N-methylnaltrexone. 2. In dogs, following the i.v. administration of N-[14C-methyl]methylnaltrexone, 50% of the radioactivity was excreted in the urine and an additional 30% in the faeces within 120 h. 3. In humans following the i.v. administration of 14C-N-methylnaltrexone, 40-60% of the radioactivity was excreted in the urine within the first 24 h. The plasma radioactivity-time curves indicated a biphasic decay and a short distribution phase between 6 and 9 min. with a longer elimination phase between 238 and 1320 min.