Partitioning of drugs

A very promising method, immobilized artificial membrane (IAM) chromatography, was developed by Pidgeon and co-workers [299-304,307], where silica resin was modified by covalent attachment of phospholipid-like groups to the surface. The retention parameters mimic the partitioning of drugs into phospholipid bilayers. The topic has been widely reviewed [47,298,307,309-311]. 

Much of the data produced in studies such as this has measured the partitioning of drugs into whole brain from blood or plasma. The importance of lipophilicity in brain distribution has therefore been highlighted in many reviews [3,4], however the majority of these have concentrated on total drug concentrations which, given the lipid nature of brain tissue, over-emphasizes the accumulation of lipophilic drugs. 

Ionisation determines the partitioning of drugs across membranes. Unionised molecules can easily cross and reach an equilibrium across a membrane, while the ionised form cannot cross. When the pH is different in the compartments separated by the membrane the total (ionised + unionised) concentration will be different on each side. An acidic drug will become concentrated in a compartment with a high pH and a basic drug in one with a low pH. This is known as ion-trapping, and occurs in the stomach, kidneys, and across the placenta. Urinary acidification accelerates the excretion of weak bases, such as pethidine, while alkalinisation increases the excretion of acidic drugs, such as aspirin. As an example consider pethidine (pKa 8.6) with an unbound plasma concentration of 100 (arbitrary units). At pH 7.4 only 6% of the pethidine will be unionised so that at equilibrium the concentration of unionised pethidine in the urine will be 6 units. In urine at pH 6.5 only 0.8% of the pethidine will be unionised so that the total concentration in the urine will be 744 units. 

In the octanofwatersystem, the partitioning of drug molecules in the neutral form is favored relative to the ionized form. In the membrane-water system, it has been found that partitioning of the ionized species is sighicantly enhanced over that shown in the octaraeter system (Miyazaki et al., 1992 ... 

Additional information, especially on the effects of solutes (drugs) on the bilayer, can be obtained by studying the partitioning of drugs into liposomes by DSC, NMR, and fluorescence techniques or other suitable spectroscopic techniques (see Chapter 3). 

C. The mechanism of PG release from the liposomal system may Involve slow partitioning of drug at the bilayer-aqueous phase interface. 

For most membranes, passive diffusion is the main mechanism by which drug traverses membrane barriers. The process of passive diffusion initially involves partition of a drug between the aqueous fluid at the site of the application and the lipoidal cell membrane. The drug in solution in the membrane then diffuses across the membrane followed by a second partition of drug between the membrane and the aqueous fluids within the site of absorption. 

However, the user needs to take into account that MDCK cells are derived from kidney. Thus, kidney specific transporters are expressed which do not play any role at the BBB. Furthermore, membrane composition is distinct in epithelial cell type (MDCK) and endothelial cells lining the brain capillaries influencing membrane partitioning of drug candidates. 

A full description of drug distribution can be complex, whether it is based on a knowledge of tissue perfusion and partition of drug from plasma to tissue, or whether it is based on a kinetic analysis of plasma concentration-time curves. One of the major descriptive parameters, which is probably of most interest to the toxicologist, is the volume of distribution (F ). This is the amount of drug in the body A) divided by the plasma concentration (c) after distribution equilibrium has been established. 

Partition of drug molecule into intestinal wall... 

Measurements of partitioning of drugs into lipid vesicles, liposomes or cell membranes as predictive models for drug absorption are also described in the literature (Hillgren et al. 1995 Balon et al. 1999 Stewart et al. 1997). This may be due to the similarity of these systems to biological membranes and the wish for a pure membrane system with the correct lipid and protein composition, but without enzymes and carrier proteins. 

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