Drug absorption unstirred layer

Avdeef, A., Nielsen, P. E., Tsinman, O. PAM PA - a drug absorption in vitro model. 11. Matching the in vivo unstirred water layer thickness by individual-well stirring in microtitre plates. Eur. J. 

Ruell, J. A. Tsinman, K. L. Avdeef, A., PAMPA—a drug absorption in vitro model. 4. Unstirred water layer in iso-pH mapping assays in pKR flux-optimized design (pOD-PAMPA) (submitted). 

The majority of evidence supporting the pH-partition hypothesis is from studies of gastrointestinal absorption, renal excretion, and gastric secretion of drugs [11]. While correlation between absorption rate and pKa was found to be consistent with the pH-partition hypothesis, deviations from this hypothesis were often reported [12]. Such deviations were explained by the existence of a mucosal unstirred layer [13,14] and/or a microclimate pH [15]. 

Fagerholm, U., Lennernas, H., Experimental estimation of the effective unstirred water layer thickness in the human jejunum, and its importance in oral drug absorption. Eur. J. Pharm. Sci. 1995, 3, 247-253. 

Fagerholm U and Lennernas H (1995) Estimation of the Unstirred Water Layer Thickness in the Human Small Intestine, and Its Importance in Oral Drug Absorption. Eur J Pharm Sci 3 pp 247-253. 

Kurosaki Y, Hisaichi S, Hamada C, Nakayama T, and Kimura T (1987) Studies on drug absorption from oral cavity. II. Influence of the unstirred water layer on absorption from hamster cheek pouch in vitro. J. Pharmacobiodyn. 10 180-187. 

Nielsen PE, Avdeef A (2004) PAMPA—a drug absorption in vitro model 8. Apparent filter porosity and the unstirred water layer. Eur J Pharm Sci 22 33—41. 

The layer of water adjacent to the absorptive membrane of the enterocyte is essentially unstirred. It can be visualized as a series of water lamellas, each progressively more stirred from the gut wall toward the lumen bulk. For BCS class 2 compounds the rate of permeation through the brush border is fast and the diffusion across the unstirred water layer (UWL) is the rate-limiting step in the permeation process. The thickness of the UWL in human jejunum was measured and found to be over 500 pm [3]. Owing to its thickness and hydrophilicity, the UWL may represent a major permeability barrier to the absorption of lipophilic compounds. The second mechanism by which the UWL functions act as a barrier to drug absorption is its effective surface area. The ratio of the surface area of the UWL to that of the underlying brush border membrane is at least 1 500 [4], i.e., this layer reduces the effective surface area available for the absorption of lipophilic compounds and hence impairs its bioavailability. 

Any enhancing effect of surfactants on drug absorption appears to be related to increased drug solubilization, modification of mucosal permeability, or reduction of resistance of the unstirred water layer at the GI membrane surface. In general, unionic surfactants have little effect on membrane structure but cationic surfactants have been associated with reversible cell loss and loss of goblet cells. These effects must limit consideration of surfactants as absorption promoters, particularly for long term treatment. 

Aqueous Boundury (Diffusion) Luyer. The aqueous boundary layer (often referred to as the stagnant, unstirred, or aqueous diffusion layer) is an important hydrodynamic barrier that a drug must traverse before reaching the surface of the mucosal membrane. " Before a molecule in the intestinal lumen passes through the membrane, it must first cross the aqueous boundary layer located at the intestinal lumen and membrane interface (Fig. 2). The liquid in this layer, in reality, is not static, as the term unstirred implies, but represents a film at the surface where diffuse and natural convective mixing occurs. This unstirred layer can be a rate-limiting step for the absorption of hydro-phobic molecules. However, hydrophilic molecules such... 

Figure 1 General pathways for drug absorption in the gut. c. Unstirred water layer...

Figure 15.1. Absorption pathways. The first common step for all pathways in GIT absorption is the diffusion throught the unstirred layers. (1) Transcellular (most common pathway for drugs), (2) paraceUular (small, water soluble compounds), (3) facihtated transport, (4) active tranport (saturable, requires ATP), and (5) efflux pumps (i.e.,pGp. MRP).

Chiou, W.L. (1994) Effect of unstirred water layer in the intestine on the rate and extent of absorption after oral administration. Biopharmaceutics ei Drug Disposition, 15, 709-717. 

FIGURE 6.1 The barriers that a lipophilic drug has to transverse along the intestinal absorption process (1) dissolution and solubilization in the intestinal milieu, (2) narrow absorption window, (3) unstirred water layer, (4) efflux pumps, (5) intra-enterocyte metabolism, and (6) first pass hepatic metabolism. 

Liu S, Tam D, Chen X, et al. P-glycoprotein and an unstirred water layer barring digoxin absorption in the vascularly perfused rat small intestine preparation induction studies with pregnenolone-16alpha-carbonitrile. Drug Metab Dispos 2006 34 1468-1479. 

In contrast to the stomach, where there is a protective pH-gradient from 7 to 1 between Ihc mucosa and the iumen hoe, there is only a slight pH gradient from about 6 (mucosa) to about 7 (lumen). It corresponds to the inner mucosal part of the unstirred water layer. The thickness of this layer is about 20 pm. The pH has no significant influence on the absorption of protein or peptide drugs. 

Briefly, upon release of the macromolecular drug from the delivery system, the drug should withstand hydrolysis and enzymatic activity in the extracellular milieu at the site of absorption. In the case of nonparenteral delivery, the unstirred water layer and especially the viscous mucin layer in particular, both present at the surface of epithelia constitute a barrier for absorption of biotechnology-based pharmaceuticals and must be permeated for the biomacromolecule to reach the surface of the epithelial membrane. A... 

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