Absorption and disposition of a tripeptoid and a tetrapeptide in the rat

The present study is concerned with the absorption and disposition of a tri peptoid (N-substituted glycine derivative) and a tetrapeptide in the rat. T he two compounds have similar backbone structures but differ with respect t o the presence or absence of peptide bond. [H-3]tripeptoid and [H-3]tetrape ptide were administered orally (30 mg kg(-1)) and intravenously (i.v.) (30 or 3 mg kg(-1)) to Sprague Dawley rats. Blood, urine and feces were collect ed at designated times for radioactivity and parent drug analysis. The inte stinal absorptive clearances of the tripeptoid and tetrapeptide were studie d using an in situ rat intestinal perfusion model. The octanol;water partit ion coefficient of these two compounds was also determined. The results sho wed that the peptoid and peptide have similar absorptive clearance and octa nol/water partitioning, but different in vivo absorption and disposition ch aracteristics. The absorptive clearances of the tripeptoid and tetrapeptide were 6.7 and 4.8 x 10(-4) mL min(-1) cm(-1), respectively, and the corresp onding octanol/water partition coefficients were 0.39 and 0.30. The extent of oral absorption of the tripeptoid was only 3-8%, consistent with its low absorptive clearance. In contrast, the apparent absorption of the tetrapep tide was > 75% of the radioactive dose. The peptide was completely metaboli zed within 2 h after an i.v. dose, whereas the peptoid was stable in blood and was primarily eliminated in feces as intact drug. In conclusion, the di fference in in vivo absorption and disposition between the peptoid and pept ide was apparently due to the presence or absence of a peptide bond. The te trapeptide was subject to rapid metabolism in the body. Its relatively high absorption appeared to represent the absorption of metabolized radioactive fragments. The peptoid appears to have advantages over the peptide in term of metabolic stability, but its low oral absorption and rapid biliary excr etion present additional challenges in the selection of an optimal drug can didate. Copyright (C) 1999 John Wiley & Sons, Ltd.