Large molecule compounds, membrane

As discussed in Chapter 3, proteins and mABs distribute initially into the plasma volume and then more slowly into the interstitial fluid space. It can be seen from Table 32.11 that the initial distribution volume of interleukin-2 (IL-2) IL-12/ granulocyte colony-stimulating factor (G-CSF)/ and recombinant tissue plasminogen activator (rt-PA) approximates that of plasma volume. In contrast/ the initial distribution volume of FIX is approximately twice that of plasma volume. On the other hand/ the volumes of distribution at steady state (Vd(ss)) for IL-12/ G-CSF/ and rt-PA are considerably smaller than is the Vd(ss) of inuliii/ a marker for extracellular fluid space (ECF). When distribution volume estimates are much less than expected values for ECF/ they could reflect the slow transport of large molecules across membranes and the fact that either assay sensitivity or sampling time has been inadequate to characterize the true elimination phase of the compound. 

Osmosis is the flow of solvent through a semipermeable membrane into a solution the osmotic pressure is proportional to the molar concentration of the solute. Osmometry is used to determine the molar masses of compounds with large molecules, such as polymers reverse osmosis is used in water purification. 

Ultra- filtration Water sample la filtered under pressure through a membrane that will pass molecular constituents below a certain size and retain those above that size. Large molecules Porosity of membrane daterminaa the size of molecules concentrated. Usually used for compounds > 1000 molecular weight. Can concentrate large sample volumes at low temperatures. 

For apolar compounds with larger Kiow values and particularly in the case of the liposomes, significantly smaller A, lipw values than predicted from Eq. 10-2 have been reported (Fig. 10.4a). This change in the observed trend may be due to a difficulty in accommodating large molecules in the structured and size-limited lipid bilayers of membranes (Opperhuizen et al., 1985). However, there may also be artifacts in the measurements. Such artifacts may involve slow uptake kinetics (i.e., observed... 

Specific transport of distinct ions and low molecular mass compounds is another prerequisite for a further development of protocells. Large molecules form within membranes as they cannot enter from the outside. The polar double layer lipid membrane is permeable for water and neutral lipids. In all events, biomembranes are crucial for formation and maintenance of primitive protocells. 

The encapsulation of drug molecules also leads to delivery systems, especially in the case of hydrophilic compounds where a permeation barrier with depot effect is provided. The permeation velocity is controlled by the properties of the membranes, as well as by the lipophilicity and size of the incorporated drug. Even large molecules are released slowly in the body, but unfortunately this also occurs under storage conditions. As liposomes do not have a solid surface, an equilibrium is built up between incorporated or adhered drug and free drug molecules, and this can lead to bursf effects when liposome dispersions are diluted. 

The rate and extent of intestinal permeation is dependent on the physicochemical properties of the compound (see Sections 16.1.2 and 16.4.3) and the physiological factors. Drugs are mainly absorbed in the small intestine due to its much larger surface area and less tight epithelium in comparison to the colon [17]. The permeation of the intestine may be affected by the presence of an aqueous boundary layer and mucus adjacent to cells, but for a majority of substances the epithelial barrier is the most important barrier to drug absorption. The lipoidal cell membrane restricts the permeability of hydrophilic and charged compounds, whereas large molecules are restricted by the ordered structure of the lipid bilayer. 

FIGURE 17.4 The blood-brain barrier. Openings in brain capillary membranes are small enough to keep out large molecules, and because the membrane contains mostly lipid molecules, ions cannot cross the membrane either. Only lipid (fat)-soluble molecules can cross unaided. These limitations provide the barrier that protects the brain from toxic compounds, but sometimes present a problem by also keeping out beneficial drugs. 

---