Rate-limiting membranes

Membrane Rate-Limiting Transport (Hydrophilic Molecules)... 

Figure 9.2 Reservoir delivery systems based on rate-limiting polymer membranes. Rate-limiting polymer membranes can be used to produce several different types of drug delivery devices including (a) transdermal delivery systems, (b) planar con-trolled-release systems, and (c) cylindrical controlled-release systems.

This system utilizes specific membranes, between which the dmg reservoir is enclosed (Fig. 4). A tiny ehiptical disk, inserted into the cul-de-sac of the eye, releases pilocarpiae steadily. The dmg is deUvered through selected polymeric membranes. The dmg reservoir maintains a saturated solution between the membranes which acts osmoticaHy as the driving force for the dmg to diffuse through the rate-limiting membranes. 

ILs, on the other hand, are uniquely suited for use as solvents for gas separations. Since they are non-volatile, they cannot evaporate to cause contamination of the gas stream. This is important when selective solvents are used in conventional absorbers, or when they are used in supported liquid membranes. For conventional absorbers, the ability to separate one gas from another depends entirely on the relative solubilities (ratio of Henry s law constants) of the gases. In addition, ILs are particularly promising for supported liquid membranes, because they have the potential to be incredibly stable. Supported liquid membranes that incorporate conventional liquids eventually deteriorate because the liquid slowly evaporates. Moreover, this finite evaporation rate limits how thin one can make the membrane. This... 

Acetylcholine serves as a neurotransmitter. Removal of acetylcholine within the time limits of the synaptic transmission is accomplished by acetylcholinesterase (AChE). The time required for hydrolysis of acetylcholine at the neuromuscular junction is less than a millisecond (turnover time is 150 ps) such that one molecule of AChE can hydrolyze 6 105 acetylcholine molecules per minute. The Km of AChE for acetylcholine is approximately 50-100 pM. AChE is one of the most efficient enzymes known. It works at a rate close to catalytic perfection where substrate diffusion becomes rate limiting. AChE is expressed in cholinergic neurons and muscle cells where it is found attached to the outer surface of the cell membrane. 

Testiculat androgens are synthesized in the interstitial tissue by the Leydig cells. The immediate precursor of the gonadal steroids, as for the adrenal steroids, is cholesterol. The rate-limiting step, as in the adrenal, is delivery of cholesterol to the inner membrane of the mitochondria by the transport protein StAR. Once in the proper location, cholesterol is acted upon by the side chain cleavage enzyme P450scc. The conversion of cholesterol to pregnenolone is identical in adrenal, ovary, and testis. In the latter two tissues, however, the reaction is promoted by LH rather than ACTH. 

Permeability-pH profiles, log Pe - pH curves in arhficial membrane models (log Pjpp - pH in cehular models), generally have sigmoidal shape, similar to that of log Dod - pH cf. Fig. 3.1). However, one feature is unique to permeabihty profiles the upper horizontal part of the sigmoidal curves may be verhcally depressed, due to the drug transport resistance arising from the aqueous boundary layer (ABL) adjacent to the two sides of the membrane barrier. Hence, the true membrane contribution to transport may be obscured when water is the rate-limiting resistance to transport. This is especially true if sparingly soluble molecules are considered and if the solutions on either or both sides of the membrane barrier are poorly stirred (often a problem with 96-well microhter plate formats). 

Lipophilicity is intuitively felt to be a key parameter in predicting and interpreting permeability and thus the number of types of lipophilicity systems under study has grown enormously over the years to increase the chances of finding good mimics of biomembrane models. However, the relationship between lipophilicity descriptors and the membrane permeation process is not clear. Membrane permeation is due to two main components the partition rate constant between the lipid leaflet and the aqueous environment and the flip-flop rate constant between the two lipid leaflets in the bilayer [13]. Since the flip-flop is supposed to be rate limiting in the permeation process, permeation is determined by the partition coefficient between the lipid and the aqueous phase (which can easily be determined by log D) and the flip-flop rate constant, which may or may not depend on lipophilicity and if it does so depend, on which lipophilicity scale should it be based ... 

The rate-limiting step in the absorption of those compounds that readily penetrate the intestinal membrane (i.e., have a large permeability coefficient) may be the rate at which blood perfuses the intestine. However, absorption will be independent of blood flow for those compounds that are poorly permeable. Extensive studies have illustrated this concept in rats [106,107]. The absorption rate of tritiated water, which is rapidly absorbed from the intestine, is dependent on intestinal blood flow, but a poorly absorbed compound, such as ribitol, penetrates the intestine at a rate independent of blood flow. In between these two extremes are a variety of intermediate compounds whose absorption rate is dependent on blood flow at low flow rates but independent of blood flow at higher flow rates. By altering blood flow to the intestine of the dog, as blood flow decreased the rate of sulfaethidole absorption also decreased [108]. These relationships are illustrated in Fig. 16. 

Usually, an increase in Cg that would affect the dissolution rate would occur only when another process, such as membrane transport or stomach emptying, becomes the rate-limiting step in drug absorption. As a general rule pharmacists should advise patients to take their oral medications with a full glass of water to ensure that dissolution occurs under optimal conditions. 

Yamashita et al. [82] also studied the effect of BSA on transport properties in Caco-2 assays. They observed that the permeability of highly lipophilic molecules could be rate limited by the process of desorption off the cell surface into the receiving solution, due to high membrane retention and very low water solubility. They recommended using serum proteins in the acceptor compartment when lipophilic molecules are assayed (which is a common circumstance in discovery settings). 

While in vivo studies assess absorption rates as process-lumped time constants from blood level versus time data, these rate parameters encompass the kinetics of dosage-form release, GI transit, metabolism, and membrane permeation. The use of isolated tissue and cellular preparations to screen for drug absorption potential and to evaluate absorption rate limits at the tissue and cellular levels has been expanded by the pharmaceutical industry over the past several years. For more detail in this regard, the reader is referred to an article by Stewart et al. [68] for references on these preparations and for additional details on the various experimental techniques outlined below. 

While both paracellular and passive transcellular pathways are available to a solute, the relative contribution of each to the observed transport will depend on the properties of the solute and the membrane in question. Generally, polar membrane-impermeant molecules diffuse through the paracellular route, which is dominated by tight junctions (Section III.A). Exceptions include molecules that are actively transported across one or both membrane domains of a polarized cell (Fig. 2). The tight junction provides a rate-limiting barrier for many ions, small molecules, and macromolecules depending on the shape, size, and charge of the solute and the selectivity and dimensions of the pathway. 

The permselectivity of the corneal and conjunctival paracellular routes was investigated by Huang et al. [159] in an attempt to show that nutrients can be extracted from the blood by the conjunctiva. Neither the blood vessels supplying the conjunctiva nor its basement membrane are rate-limiting to the transport of horseradish peroxidase. This 40 kDa tracer is restricted underneath the conjuncti-... 

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