MULTIPLE-MODEL EVALUATION OF ABSORPTION OF A TACHYKININ RECEPTOR ANTAGONIST

This paper describes a case study examining the absorption of a tachyk inin antagonist. Cam-2445, an NK1 receptor antagonist with high lipoph ilicity and low aqueous solubility, was the prototype. Several in vitr o and in situ models were utilized prior to in vivo evaluation. Cam-24 45 was incubated in various intestinal preparations or pure enzymes to estimate stability in the GI tract. Intestinal permeability was exami ned in Caco-2 cells and in a rat intestinal perfusion model. Cam-2445 was also incubated in rat hepatocytes to evaluate liver extraction. Th e compound was subsequently administered as a solution to rats by intr avenous, oral, intraduodenal, or intraportal routes. Cam-2445 was rela tively stable in various biological matrices and high intestinal perme ability was observed, suggesting that the dissolved compound was readi ly absorbed from the intestine. Hepatic extraction was significant, bu t not limiting. The results strongly supported that precipitation in t he GI tract resulted in poor oral bioavailability in rats.