The impact of bile acid sequestrants on octreotide absorption

Despite significant advancements in peptide drug development, there is still a challenge in formulating and delivering peptide drugs orally. Current oral peptide drugs have very low bioavailability (<1%), which could be attributed, in part, to enzymatic instability, poor membrane permeability/flux, and the sequestration by intestinal colloids composed of bile acid and phospholipids that form bile acid-phospholipid mixed micelles (BAPMM). In this work, we examined the effect of perturbing the BAPMM with bile acid sequestrants (BAS) on the membrane flux and enzymatic stability of octreotide in vitro, and its potential impact on peptide absorption and bioavailability in vivo. Additionally, we tested the effect of adding cyclic E-cadherin peptide (ECP) permeation enhancers on the bioavailability of octreotide. The results suggest that using BAS decreases the bile acid levels and putatively disrupts the micellar structure, leading to a higher concentration of the free peptide to diffuse across the membrane. In vitro bile acid sequestration enhanced the overall peptide flux rate without compromising the improved enzymatic stability. Our in vivo data suggests that using the BAS, colestipol, did not have a significant impact on peptide absorption though. These results highlight the important role of BAPMM on bioaccessible drug concentration, as well as membrane permeation.