Rising dose proportionality of enadoline (CI-977) in rats and dogs

The rising-dose proportionality pharmacokinetics, after intramuscular (IM) administration of CI-977, an active, analgesic, kappa opioid receptor agoni st, were evaluated in fed male Wistar rats and beagle dogs. Following NIH guidelines, jugular vein cannulas were surgically implanted i n 24 male Wistar rats, After recovery following the surgery, single doses o f 0.04, 0.1, 1.0, or 2.0 mg/kg of CI-977 (free-base equivalents) were given IM to six rats at each individual dose level, In an identical paradigm, si x beagle dogs (3 male; 3 female) were given single IM doses of 0.3, 1.0, 3. 0, 15.0, and 45 mu g/kg of CI-977, Blood samples (0.25 mt for rats and 4 mt for dogs) were collected into heparinized syringes for 24 hours after dosi ng, and plasma was analyzed using separately validated radioimmunoassay pro cedures, CI-977 was rapidly absorbed after IM administration in both species, In rat s, following the absorption phase, plasma CI-977 concentrations declined in an apparent biexponential fashion. Areas under the plasma concentration-ti me curves (AUC[0-->24 hour]) and C-max data suggested a trend toward greate r than dose proportional increases in CI-977 exposure with increasing dose in rats, In dogs, the mean terminal elimination half-lives ranged from 41.2 minutes at the 0.3 mu g/kg doses to 124 minutes after the 45 mu g/kg dose. AUC(0-->infinity) increased with dose from 9.94 ng.min/mL at 0.3 mu g/kg t o 1360 ng.min/mL at 45 mu g/kg. The increases in C-max and AUC(0-->infinity ) were proportional to dose.