Peptide intestinal uptakes

The conjugation of vitamin B12 has been shown to increase oral bioavailability of peptides, proteins, and particles.44 46 62,63 Russsell-Jones and coworkers have attempted to exploit RME of vitamin B12 for the enhanced intestinal uptake of macromolecules such as luteinizing hormone—releasing factor (LHRH), granulocyte colony-stimulating factor, erythropoietin, and a-interferon.44,46,63 Also, they demonstrated that surface modification of nanoparticles with vitamin B12 can increase their intestinal uptake.44,62 The extended applications of this unique transport system, however, appear partially hampered by its limited uptake capacity. In human being, the uptake of vitamin B12 is only 1 nmol per intestinal passage. 

The vitamin B12 receptor which facilitates uptake of the vitamin-intrinsic factor vitamin-binding protein complex has been used to enhance oral delivery and gastrointestinal uptake of peptides and proteins as their vitamin B12 conjugates (37). Commercial efforts are under way to exploit this receptor as well as the fetal Pc receptor which facilitates intestinal uptake of antibodies from colostrum/milk (38) and the polymeric immunoglobulin receptor which facilitates the serosal to mucosal transport of IgA and IgM (39). 

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Wenzel, U., D. T. Thwaites, and H. Daniel. Stereoselective uptake of beta-lactam antibiotics by the intestinal peptide transporter. Br. ]. Pharmacol. 1995, 116, 3021-3027. 

Bretschneider, B., M. Brandsch, and R. Neubert. Intestinal transport of beta-lactam antibiotics analysis of the affinity at the H+/peptide symporter (PEPT1), the uptake into Caco-2 cell monolayers and the transepithelial flux. Pharm. Res. 1999, 16, 55-61. 

Groneberg DA, Doring F, Eynott PR, et al. Intestinal peptide transport ex vivo uptake studies and localization of peptide carrier PEPT1. Am J Physiol Gastrointest Liver Physiol 2001 28LG697-G704. 

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PURPOSE AND RATIONALE During the last 10 years many uptake transporters as well as efflux transporters have been discovered in the GI and especially in the small intestine. They allow uptake of ions, amino acids, peptides, nucleic acids, sugars, organic acids, vitamins, cofactors and nucleosides. On the other hand, efflux transporters ensure protection of the organism from unwanted pathogen or compound delivery. Subsequently, cellular systems have been used to study uptake in mechanistic studies in more detail. Additionally inhibition studies provide hints on potential drag-drug interactions. 

Balimane P, Sinko P (2000), Effect of ionization on the variable uptake of valacyclovir via the human intestinal peptide transporter (hPepTl) in CHO cells. Biopharm Drug Dispos 21 165-174... 

Remikiren (Figure 1.6a) is effective but has several shortcomings, such as low bioavailability - which means that the drug does not efficiently get into the systemic circulation after oral uptake. Of course, oral application is quite essential in the treatment of long-term conditions such as hypertonia. A major cause of low bioavailability of dmgs is their metabolic inactivation. Dmg metabolism mostly happens in the liver (and sometimes in the intestine) and often is a major limiting factor of a dmg s clinical usefulness. Remikiren contains several peptide bonds, which likely are a target for enzymatic hydrolysis. 

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