Figure 1 represents a typical drug concentration-time PK profile after oral administration. The Cmax and the time to achieve the peak concentration (Tmax) can be estimated from this profile. For the purpose of simplicity, a one-compartment model leads to the following expressions for Tmax and Cmax (the same concept applies to other compartment or noncompartment models):

Vd where ke and ka are the first-order elimination and absorption constants, respectively; Vd is the volume distribution; Dose is the oral dose; and F is the absolute bioavailability (expressed in fraction). In turn, the bioavailability F is given by

where fabs is the fraction of drug absorbed into the GI wall, fGI is the fraction metabolized in the GI (preabsorption in lumen and intracellular), and fH is the fraction extracted during the first-pass hepatic metabolism.

Despite the high level of activity in peptide-based drug research, imparting good bioavailability while maintaining pharmacological efficacy is one of the key challenges that have hindered the development of peptides into useful

FIGURE 1 A representative pharmacokinetic profile of oral protein and peptide therapeutics, showing one-compartment model.

therapeutic products. The oral administration of peptide and protein drugs faces two formidable problems. The first is the protection against the metabolic barriers of the GI tract. The entire GI tract and the liver are designed to metabolize and break down proteins and peptides into smaller fragments of 2 to 10 amino acids using a variety of proteolytic enzyme (proteases). There are four major types of enzymes of concern: aspartic proteases (pepsin, rennin), cystine proteases (papain, endopeptidase), metallo proteases (carboxypeptidase-A, ACE), and serine proteases (thrombin, trypsin). The second problem is the absence of a carrier system for absorption of peptides with more than three amino acids. Pharmaceutical approaches to address drug permeation across these barriers that have been successful with traditional smaller organic drug molecules cannot be readily developed into effective protein and peptide formulations. Designing and formulating a protein and peptide drug delivery for the GI tract has been a formidable challenge because of these unfavorable physicochemical properties of enzymatic degradation and poor membrane permeability.

The development of oral drug delivery technologies to improve the absorption of peptide and protein drugs is one of the greatest challenges in drug development. The next section reviews the following approaches to deliver therapeutic protein and peptide drugs: (i) chemical modifications of protein and peptide drugs, (ii) formulation additives to enhance the GI absorption of protein and peptide drugs, and (iii) dosage form design that protects protein and peptide drugs from GI metabolism. In addition, combination of these approaches can further maximize the overall drug bioavailability. Those approaches have been described in a number of excellent review articles that readers are referred to for additional details (1,12-27).

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