Peptide carrier system

Hu Ming, HI Mosberg, GL Amidon. Use of the peptide carrier system to improve the intestinal absorption of L-alpha-methyldopa Carrier kinetics, intestinal permeabilities, and in vitro hydrolysis of dipeptidyl derivatives of L-alpha-methyldopa. Pharm Res 6(1) 66—69, 1989. 

M Hu. Investigation into drug and drug analogs transported by the peptide carrier system Intestinal absorption of captopril and of peptidyl derivatives of methyldopa. PhD Thesis, College of Pharmacy, University of Michigan, 1988. 

A series of peptide prodrugs ofh-a-methyldopa were prepared and shown to exhibit high affinity for the peptide carrier system [32], In an in situ intestinal perfusion model, the prodrugs Phe-L-a-methyldopa (6.10) and l-a-methyldopa-Phe (6.11) showed permeabilities that were 10- and 20-times higher, respectively, than that of L-a-methyldopa. The other derivatives examined (Gly- and Pro-L-a-methyldopa, L-a-methyldopa-Pro) also had better permeabilities. These and other results indicate that the peptide transport system has a relatively low substrate specificity and can indeed be targeted by peptide prodrugs to improve absorption [33],... 

M. Hu, P. Subramanian, H. I. Mosberg, G. L. Amidon, Use of the Peptide Carrier System to Improve the Intestinal Absorption of L-a-Methyldopa Carrier Kinetics, Intestinal Permeabilities, and in vitro Hydrolysis of Dipeptidyl Derivatives of L-a-Methyldopa , Pharm. Res. 1989, 6, 66-70. 

Kingsbury, W. D., Boehm, J. C., Mehta, R. J., Grappel, S. R Transport of antimicrobial agents using peptide carrier systems anticandidal activity of m-fluorophenylalanine peptide conjugates. J. Med. Chem. 1983,26,1725-1729. 

Since our backbone 2 aPNA incorporates six Lys residues in its peptide sequence and is cationic at a physiological pH, we were optimistic that this aPNA would be taken up into cells without the need for any external carrier system. To answer the simple question of whether b2 aPNAs are intemahzed, a standard fluorescence microscopy experiment was performed to see if whole cells that were incubated with a fluorescent-labeled aPNA would internahze labeled material [70]. Chinese Hamster Ovary (CHO) cells in culture were incubated with BODIPY-la-beled TCCCT(b2) at 37 °C for various periods of time. Following incubation, the cells were rinsed in phosphate-buffered sahne (PBS), fixed with 4% formaldehyde at ambient temperature for 20 min, then washed with PBS and stored in a refrigerator until examined by fluorescence microscopy. 

Enalaprilat and SQ27,519 are angiotensin-converting enzyme (ACE) inhibitors with poor oral absorption. Enalapril and fosinopril are dipeptide and amino acid derivatives of enalaprilat and SQ27,519, respectively [51] (Fig. 10). Both prodrugs are converted via deesterification to the active drug by hepatic biotransformation. In situ rat perfusion of enalapril indicated a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast to the active parent, enalapril renders enalaprilat more peptide-like, with higher apparent affinity for the peptide carrier. The absorption of fosinopril was predominantly passive. Carrier-mediated transport was not demonstrated, but neither was its existence ruled out. 

On the other hand, several probe substrates of carrier-mediated transport systems in the small intestine have been reported to be not absorbed by carrier-mediated mechanism in the rat colon in situ. Those include L-carnitine [23], methotrexate [18], cephradine [18], and 5-fluorouracil [18], as substrates of the L-carnitine carrier, folate carrier, peptide carrier, and pyrimidine carrier, respectively (Table 3.3). It is based on the nonsaturable nature of their transport. Particularly, the apparent membrane permeabilities of L-carnitine and methotrexate are negligibly low, suggesting that these compounds are practically unabsorbable from the colon. In the case of 5-fluorouracil, Na+-independence of transport was observed in situ [18] and also in everted sacs in vitro in the colon [21], while its carrier in the small intestine is known to be Na+-dependent. Furthermore, for ascorbate and nicotinate, as described in everted sacs in vitro [21], and L-dopa, as described in situ [24], carrier-mediated transport cannot be observed in the rat colon. 

There have been sustained efforts in recent years to use the carrier systems of the brush-border membrane of intestinal mucosa to increase absorption of orally administered drugs [29] [30]. One system of particular interest is the intestinal peptide carrier (hPEPTl) whose physiological function is the absorption of di- and tripeptides and whose xenobiotic substrates include /3-lactam antibiotics, renin inhibitors, and angiotensin-converting enzyme (ACE) inhibitors [31]. 

Amino acids and some small peptides are absorbed into the enterocytes in the jejnnnm. The transport of amino acids from the lumen into the ceU is an active process, coupled to the transport of Na ions down a concentration gradient. There are at least six carrier systems with different amino acid specificities neutral amino acids (i.e. those with no net charge, e.g. branched-chain amino acids) neutral plus basic amino acids imino acids (proline, hydroxyproline) and glycine basic amino acids (e.g. arginine and lysine) P-amino acids and taurine acidic amino acids (glutamic and aspartic acids). 

Numerous problems in the construction of chnically applicable drug targeting moieties still need to be solved. Of these issues, immunogenicity after repeated administration, counterproductive hver clearance, and production 5delds are the most important. Although the problem of immunogenicity is beheved to have been solved for monoclonal antibody therapy by the development of humanized and fully human antibodies [110], for other carrier systems such as modified plasma proteins and peptide modified polymers, this remains an important issue. 

E. Walter, T. Kissel, and G. E. Amidon. The intestinal peptide carrier a potential transport system for small peptide-derived drugs. Adv. Drug Deliv. Rev. 20 33—58, 1996. 

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