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

Abstract

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.

Metabolic Fate of Lactoferricin-Based Antimicrobial Peptides: Effect of Truncation and Incorporation of Amino Acid Analogs on the In Vitro Metabolic Stability

“…5. Although the present study is not aimed at optimizing the metabolic stability, approaches are available to the medicinal chemist to increase the metabolic resistance against degradation as described recently (Bernkop-Schnü rch and Schmitz, 2007). Acylation of the N-terminal amine, for example, may increase the stability toward aminopeptidase B.…”

“…If it is revealed that a specific enzyme is responsible for the bulk of the degradation, then inhibitors such as pepstatin, bestatin, leupeptin, and chymostatin can be coadministered to deal with the specific enzymes. Several problems can arise from this type of inhibitor coadministration though, and it is not a general solution acceptable in the pharmaceutical field (Bernkop-Schnü rch and Schmitz, 2007). Maintaining the tripeptide sequence is a strategy to minimize the interactions with peripheral binding pockets on the main proteolytic enzymes, and a continued focus on arginine and tryptophan analogs may actually prove to be the simplest approach.…”

Amides from Piper as a Diuretic: Behind the Ethnopharmacological Uses of Piper glabratum Kunth

“…This difference may involve factors which account for gender-related pharmacokinetic differences. Furthermore, the fact that orally the MEPG presents an LD50 above 3000 mg/kg may be due to difference in route of entry, which allows the drug to undergo presystemic metabolism before reaching the target tissue [16]. …”

In Vitro and In Vivo Human Metabolism of Degarelix, a Gonadotropin-Releasing Hormone Receptor Blocker

“…Brush border membrane of intestinal mucosal cells contains a peptide carrier system with rather broad substrate specificity and various endo-and exopeptidase activities (Bai and Amidon, 1992;Bernkop-Schnürch and Schmitz, 2007). Similar membrane-bound enzymes might be responsible for the transport and the degradation of degarelix.…”