Transcellular absorption, peptides

Penetration enhancers are low molecular weight compounds that can increase the absorption of poorly absorbed hydrophilic drugs such as peptides and proteins from the nasal, buccal, oral, rectal, and vaginal routes of administration [186], Chelators, bile salts, surfactants, and fatty acids are some examples of penetration enhancers that have been widely tested [186], The precise mechanisms by which these enhancers increase drug penetration are largely unknown. Bile salts, for instance, have been shown to increase the transport of lipophilic cholesterol [187] as well as the pore size of the epithelium [188], indicating enhancement in both transcellular and paracellular transport. Bile salts are known to break down mucus [189], form micelles [190], extract membrane proteins [191], and chelate ions [192], While breakdown of mucus, formation of micelles, and lipid extraction may have contributed predominantly to the bile salt-induced enhancement of transcellular transport, chelation of ions possibly accounts for their effect on the paracellular pathway. In addition to their lack of specificity in enhancing mem-... 

Recent years have witnessed an explosive growth in the imderstanding of the mechanisms associated with the absorption of drugs, especially therapeutic peptides and proteins. Scientists from a variety of disciplines continue to elucidate the variables associated with the optimal formulation and delivery of drugs via the oral mucosa. A greater rmderstanding of the para- and transcellular route of drug absorption, pro-... 

Burton, P.S., Conradi, R.A. and Hilgers, A.R. (1991) Mechanisms of peptide and protein absorption. (2). Transcellular mechanism of peptide and protein, absorption passive aspects. Advanced Drug Delivery Reviews, 7, 365-386. 

The second reason to consider the intracellular enzymes is because of the absorption mechanisms by which macromolecules may cross the intestinal mucosa. There are two possible mechanisms for relatively small macromolecules such as therapeutic peptides and oligonucleotides, they may be able to pass via the paracellular route between the cells, particularly if some absorption enhancers are present. For example, Tsutsumi et al. (2008) have shown in vitro that in the presence of chenodeoxycholate as an absorption enhancer modified oligonucleotides with molecular weights of nearly 3,700 and 7,400 Da could cross rat intestine via the paracellular route. In the case of the paracellular route the macromolecules will not be exposed to the intracellular enzymes and thus they will not be subject to intracellular hydrolysis. However, macromolecules, especially larger ones, will cross the epithelium via the transcellular mechanism of endocytosis. In this case they will be taken into the lysosomes that contain a formidable array of digestive enzymes (see later in Section 1.5.2). 

The oral bioavailability of a peptide was improved from 0.5 to 27% due to the co-administration of MCG (Constantinides et al. 1994). Lundin et al. (1997) demonstrated that monohexanoin is even more effective than MCG in increasing oral absorption of the therapeutic peptide dDAVP in rats. Furthermore, due to the co-administration of a monoolein/sodium taurocholate combination the colonic uptake of polyethylene glycol 4000, calcitonin and horseradish peroxidase in rats was significantly increased without causing morphologic damage to the mucosa. The appearance of horseradish peroxidase in the cytoplasm suggested enhancement via the transcellular route of uptake (Hastewell et al. 1994). 

Other transcellular mechanisms of absorption include carrier-mediated transport and endocytic processes. Although it is well known that carrier-mediated transport systems exist for di- and tripeptides in the intestine, there is still no evidence for carrier-mediated transport of peptides across the vaginal mucosa, although prostaglandins have been demonstrated to utilize such a mechanism. Although there must be some type of endocytic transport of endogenous peptides into the epithelial cells in order to regulate proliferation, no receptor-mediated or bulk-fluid mechanisms have been reported. 

Peptides and Proteins Oral Absorption ----------Transcellular route-------- ... 

There does not appear to be any significant proteolytic degradation by enzymes in the extracellular fluid in normal human airways and alveoli. However, the presence of peptidases makes absorption of small peptides variable and difficult to predict. Peptidase-resistant peptides generally show better bioavailabilities than other peptides with comparable molecular weights. ° Difference in metabolism and absorption of d and L forms of peptides glycyl-D-phenylalanine and glycyl-L-phenylalanine was demonstrated by Morimoto et al.f The l peptide was subject to metabolism, and it had significant paracellular transport with a smaller transcellular component. In contrast, the... 

Enhancement of drug uptake by altered junctional (paracellular) or vesicular (transcellular) transport (Fig. 2) is an active area of research [22,23], The paracellular transport mechanism provides an explanation for the pulmonary absorption of peptides and proteins <40 kDa. 

Permeation enhancers improve the absorption of protein and peptides by increasing their paracellular and transcellular transports. An increase in paracellular transport is mediated by modulating the tight junctions of the cells, and an increase in transcellular transport is associated with an increase in the fluidity of the cell membrane. Chapter 2 describes in depth the various paracellular and transcellular transport pathways, which will not be discussed here. 

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