Metabolic barrier

J Wacher, L Salphati, LZ Benet. Active secretion and enterocyte drug metabolism barriers to drug absorption. Adv Drug Del Rev 20 99-112, 1996. 

The focus of this chapter is on the penetration barrier. The metabolic barrier due to esterases [39-41], aminopeptidases [38], and ketone reductase [43,51] has been reviewed elsewhere [52], The present chapter reviews and describes the... 

Although the absence of paracellular transport across the BBB impedes the entry of small hydrophilic compounds into the brain, low-molecular-weight lipophilic substances may pass through the endothelial cell membranes and cytosol by passive diffusion [7]. While this physical barrier cannot protect the brain against chemicals, the metabolic barrier formed by the enzymes from the endothelial cell cytosol may transform these chemicals. Compounds transported through the BBB by carrier-mediated systems may also be metabolized. Thus, l-DOPA is transported through the BBB and then decarboxylated to dopamine by the aromatic amino acid decarboxylase [7]. 

In addition to the intercellular lipids of the buccal mucosa, there appear to be other barriers which may reduce the ability of an exogenous compound to permeate the buccal mucosa. These include the salivary film and mucus layer, the basement membrane, and a metabolic barrier. 

Another interesting feature of nutritargeting is the ability to circumvent absorption or metabolization barriers during malabsorption, maldigestion, or when there is a lack of transport proteins, for example, tocopherol-... 

Enzyme inhibitors can reduce the metabolic barrier to nasal delivery. The selection of an inhibitor is made on the basis of its ability to inhibit effectively the enzyme primarily responsible for the degradation of a particular compound. The coadministration of peptidase and protease inhibitors such as bacitracin, bestatin, amastatin, and aminoboronic acid derivatives has been found to promote the absorption of LHRH and growth hormone [42,43]. Aminopeptidase inhibitors in particular are effective in improving the bioavailability of enkephalins [44]. 

Ashton, P., W. Wang, and V.H.L. Lee. 1991. Location of penetration and metabolic barriers to levobunolol in the corneal epithelium of the pigmented rabbit. J Pharmacol Exp Ther 259 719. 

Wacher, V. J., Salphati, L., and Benet, L. Z. Active secretion and enterocytic drug metabolism barriers to drug absorption. Ado. Drug Deliv. Rev. 46(1—3) 89—102, 2001. 

The administration of drugs by alternative routes avoids absorption and metabolic barriers that may be present in the GI tract. The routes can also provide systematic availability when oral administration is contraindicated due to a physiologic condition, or the route may provide for a concentration-time profile that approaches intravenous dosing profiles. The ophthalmic, nasal, pulmonary, buccal, transdermal, and rectal routes provide one or more of these advantages. 

Minn, A. Leclerc, S. Heydel, J.M. Minn, A.L. Denizcot, C. Cattarehi, M. Netter, P. Gradinaru, D. Drug transport into the mammalian brain the nasal pathway and its specific metabolic barrier. J. Drug Target. 2002, 10 (4), 285-296. 

Within the lumen of the stomach, a mixture of hydrochloric acid and proteolytic pepsins is the first metabolic barrier that a peptide drug will encounter. 

The main component of the blood-brain barrier is the brain endothelium, which exhibits a physical, an efflux and a metabolic barrier for the transport of drugs into the CNS. The physical barrier, an efflux, is a result of the tight junctions between adjacent endothelial cells, which are around 50-100 times tighter than in the peripheral endothelium, so that penetration across the endothelium is effectively confined to transcellular mechanisms [26, 27]. These junctions significantly restrict even the movement of small ions such as Na" " and Cl , so that the transendothelial electrical resistance (TEER), which is typically 2-20 2 cm in peripheral capillaries, can be over 1000 1 cm in brain endothelium [28]. 

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