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

Abstract

ABSTRACT:The present study is concerned with the absorption and disposition of a tripeptoid (N-substituted glycine derivative) and a tetrapeptide in the rat. The two compounds have similar backbone structures but differ with respect to the presence or absence of peptide bond. ) and intravenously (i.v.) (30 or 3 mg kg − 1 ) to Sprague Dawley rats. Blood, urine and feces were collected at designated times for radioactivity and parent drug analysis. The intestinal absorptive clearances of the tripeptoid and tetrapeptide were studied using an in situ rat intestinal perfusion model. The octanol/water partition coefficient of these two compounds was also determined. The results showed that the peptoid and peptide have similar absorptive clearance and octanol/water partitioning, but different in vivo absorption and disposition characteristics. The absorptive clearances of the tripeptoid and tetrapeptide were 6.7 and 4.8 ×10 − 4 mL min, respectively, and the corresponding 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 tetrapeptide was \ 75% of the radioactive dose. The peptide was completely metabolized 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 difference in in vivo absorption and disposition between the peptoid and peptide was apparently due to the presence or absence of a peptide bond. The tetrapeptide 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 excretion present additional challenges in the selection of an optimal drug candidate.

Toward a clinical antifungal peptoid: Investigations into the therapeutic potential of AEC5

“…Antifungal peptides also generally act through membrane disruption, but may also cause fungal cell death through cell wall disruption or through intracellular (IC) targets that result in ROS generation or programmed cell death . Reports of peptoids in vivo indicate that they have poor oral bioavailability, excellent tissue absorption, slow elimination through the feces, long half‐lives, and limited toxicity, at least when tested acutely . One of these studies demonstrates the in vivo antibacterial efficacy of a peptoid, with an average two log order reduction in bacterial counts in mice compared to saline controls .…”

Synthesis and structure–activity relationship studies of peptidomimetic PKB/Akt inhibitors: The significance of backbone interactions

“…Peptoid analogs have shown higher selectivity, 15 improved potency 15 and superior pharmacological properties. 16,17 N a -Methylation (Fig. 1) is a powerful tool for structure-activity relationship studies and is often used to examine the effects of local backbone modifications on the potency of a known peptide sequence.…”

Peptoids: Bio-Inspired Polymers as Potential Pharmaceuticals

“…Aside from toxicity, the metabolic fate of peptoids needs to be determined through biodistribution studies. Tse and co-workers in 1999 showed that a trimer peptoid had low oral absorption and was excreted intact into the feces in 2 h [157]. To understand the fate of the peptoids in vivo, similar detailed studies need to be conducted using structurally and sequentially different, and active and inactive peptoids.…”