Peptides, poor bioavailability

Despite their favourable properties, peptide-based drugs are under-represented in the pharmaceutical market. This discrimination is usually due to their poor bioavailability, which sometimes necessitates non-oral administration or even special medical devices such as inhalers. Another related major disadvantage of peptides is their low metabolic stability due to proteolytic degradation, hi addition, costs of goods for the drug substance are sometimes tremendous. Therefore, there is considerable interest to transform the active principle of biologically active peptides into small molecules with improved pharmacokinetic properties, hi this chapter, we present an overview of... 

The addition of sugar moieties to peptides and other drug candidates with poor bioavailability has three major benefits ... 

A major problem with peptide-based modulators of protein-protein interactions is that they are vulnerable to proteolytic cleavage and thus have poor bioavailability. Different strategies have been used to overcome this problem. For example, peptides in which L-amino acids at potential protease cleavage sites are replaced by D-amino acids or constrained analogs have improved half-lives in cellular assays. However, these methods have serious limitations as the... 

All of the hematopoietic growth factors are proteins with molecular weights greater than 15,000. Like other proteinaceous drugs, the growth factors cannot be administered orally because they have such poor bioavailability. Their peptide bonds are destroyed by stomach acid and digestive enzymes. 

The search for an effective non-peptide oxytocin antagonist has become a major goal of a number of pharmaceutical companies because of the poor pharmacokinetic properties and especially the lack of oral bioavailability associated with peptidic antagonists. Early research in this field was dominated by Merck, but in recent years significant research efforts at GlaxoSmithKline and Serono have been published. A number of other companies, notably Sanofi-Aventis, Yamanouchi and Wyeth, have had a major presence in vasopressin receptor research and oxytocin is frequently included in patent claims for the molecules. Occasionally, oxytocin-selective compounds have been reported, usually derived by adaptation of the vasopressin antagonist template. 

Instead of using the oral bioavailability of a drug, one can attempt to correlate PM values with permeability coefficients generated from in situ perfused intestinal preparations. Here, one eliminates the complexities of liver metabolism, clearance, and formulation variables. Recently, this type of in vitro-in situ correlation has been conducted using the model peptides (described previously in Section V.B.2). The permeabilities of these model peptides were determined using a perfused rat intestinal preparation which involved cannulation of the mesenteric vein (Kim et al., 1993). With this preparation, it was possible to measure both the disappearance of the peptides from the intestinal perfusate and the appearance of the peptides in the mesenteric vein. Thus, clearance values (CLapp) could be calculated for each peptide. Knowing the effective surface area of the perfused rat ileum, the CLapp values could be converted to permeability coefficients (P). When the permeability coefficients of the model peptides were plotted as a function of the lipophilicity of the peptides, as measured by partition coefficients in octanol-water, a poor correlation (r2 = 0.02) was observed. A better correlation was observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptide can make with water (r2 = 0.56,... 

Proteolytic enzymes in the respiratory mucosa play important role(s) in the regulation of lung inflammation and remodelling [123, 124], Pulmonary proteolytic enzymes, however, also comprise one of the barriers which pulmonary-administered protein/peptide drugs have to overcome in order to achieve adequate bioavailability [125]. Intriguingly, the pulmonary enzymatic barrier is an aspect that has been little investigated and is poorly understood. Inconsistencies in the data available to date are most likely a result of the use of different techniques (e.g., PCR, immunotechniques and enzyme activity assays), different species and different cell (pheno)types, for example primary cells vs. cell lines. 

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