Presystemic Metabolism of Orally Administered Peptide Drugs and Strategies to Overcome It

To date, the majority of therapeutic peptides and proteins have to be administered via parenteral routes, which are painful and inconvenient. Consequently, “injectable-to-oral-conversions” are highly on demand. Apart from a poor membrane uptake, however, an extensive presystemic metabolism of orally given peptide drugs is responsible for a comparatively very poor oral bioavailability. This presystemic metabolism in the gastrointestinal tract is based on luminally secreted enzymes (I) including pepsins, trypsin, chymotrypsin, elastase and carboxypeptidase A/B, on brush border membrane bound enzymes (II) including various carboxypeptidases and aminopeptidases and on cytosolic enzymes (III). In addition, thiol-disulphide exchange reactions between orally administered peptide drugs and sulfhydryl bearing components of the gastrointestinal juice are responsible for a presystemic metabolism. Strategies to avoid a presystemic metabolism in the gastrointestinal tract are on the one hand based on chemical modifications of peptide drugs in order to make them more stable towards an enzymatic attack. On the other hand various formulation techniques are applied in order to protect therapeutic peptides, being incorporated in appropriate carrier systems. They include liposomes, nano-/microparticles and matrix tablets comprising various auxiliary agents such as enzyme inhibitors and multifunctional polymers. Within this review an overview about “the enemy's strength” and the current strategies to avoid a presystemic metabolism of orally administered peptides is provided.