ABSORPTION OF CAM-2445, AN NK1 NEUROKININ RECEPTOR ANTAGONIST - IN-VIVO, IN-SITU, AND IN-VITRO EVALUATIONS

Cam-2445 is a selective, high-affinity NK1 receptor antagonist that is a potentially useful treatment for arthritis, asthma, migraine, anxie ty, psychosis, and emesis. Cam-2445 exhibits low aqueous solubility an d high lipophilicity and has a molecular weight of 470. Cam-2445 has p oor oral bioavailability and the purpose of this research was to exami ne the potential barriers to the oral bioavailability of Cam-2445. Cam -2445 was relatively stable at 37 degrees C in 0.1 N HCl, 5 mu M alpha -chymotrypsin, rat intestinal perfusate, and in rat jejunal brush bord er membrane suspension. High permeability was observed from CACO-2 cel ls and from rat single-pass intestinal perfusions. Cam-2445 was admini stered as a solution to rats by intravenous (iv), oral (po), intraduod enal (id.), and intraportal (ipv) routes. The total oral bioavailabili ty was poor at 1.4%. Absorption appeared to be rapid after id, dosing; bioavailability was 26%, and 54% of the dose was absorbed intact into the portal system. After ipv dosing, 48% of the dose was available to the systemic circulation. The elimination t(1/2) after id. dosing (2. 98 h) was comparable to that after iv dosing (2.93 h), whereas it was significantly longer after pc dosing (12.4 h). The po dose apparently precipitated in the gastrointestinal (GI) tract, resulting in low oral bioavailability. These results indicated that neither stability in th e GI tract nor membrane transport were major obstacles to the absorpti on of Cam-2445. While hepatic extraction of 52% was significant, the l ow aqueous solubility of Cam-2445, as well as the differences noted be tween po and id. studies, strongly support Gi dissolution and/or preci pitation as the limiting factor for the oral bioavailability of the co mpound.