Proteins distribution barriers

Bours J. The protein distribution of bovine, human and rabbit aqueous humour and the difference in composition before and after disruption of the blood/aqueous humour barrier. Lens Eye Toxic Res 1990 7(3—4) 491—503. 

If solutions on two sides of a membrane contain different concentrations of ions that cannot freely move through the membrane (e.g., proteins), distribution of the diffusible ions (e.g., electrolytes) at the steady state wfll be unequal, but the product of the concentrations of ions in one compartment is equal to the product of ions in the other compartment (Gibbs-Donnan law). Also the law of electrical neutrality is obeyed for both compartments. An example of the uneven distribution of an ion in two compartments with different protein content (nondiffusible ions) is the concentration of chloride ions in plasma and CSF. As a result of the increased selectivity of the blood-brain barrier against proteins, Cr ions are -15% higher in CSF to estabflsh electrical and osmotic equflibrium. Calculations that demonstrate these principles can be found in the first edition of this textbook (pp. 1225-1227). ... 

Figure 5,4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details...

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

P-glycoprotein, a plasma membrane transport protein, is present in the gut, brain, liver, and kidneys 42 This protein provides a biologic barrier by eliminating toxic substances and xenobiotics that may accumulate in these organs. P-glycoprotein plays an important role in the absorption and distribution of many medications. Medications that are CYP3A4 substrates, inhibitors, or inducers are also often affected by P-glycoprotein therefore, the potential for even more DDIs exists in transplant recipients.42... 

Pharmacodynamics Duration 1-4 weeks Absorption IM slow Time to peak serum levels 12-24 hours Duration 15-24 hours Absorption IM slow Distribution Poor blood-brain barrier penetration, enters breast milk Metabolism =30% hepatic inactivation Protein binding 65% Time to peak serum levels 1-4 hours Excretion Urine (60-90% as unchanged drug) Clearance Renal... 

Figure 3 A hydrophobic permeant must negotiate through a complex series of diffu-sional and thermodynamic barriers as it penetrates into a cell. The lipid and protein compositions and charge distribution of the inner and outer leaflets of the membrane lipid bilayer can play limiting roles, particularly at the tight junction. Depending upon the permeant s characteristics, it may remain within the plasma membrane or enter the cytoplasm, possibly in association with cytosolic proteins, and partition into cytoplasmic membranes.

Once in the serum, aluminium can be transported bound to transferrin, and also to albumin and low-molecular ligands such as citrate. However, the transferrrin-aluminium complex will be able to enter cells via the transferrin-transferrin-receptor pathway (see Chapter 8). Within the acidic environment of the endosome, we assume that aluminium would be released from transferrin, but how it exits from this compartment remains unknown. Once in the cytosol of the cell, aluminium is unlikely to be readily incorporated into the iron storage protein ferritin, since this requires redox cycling between Fe2+ and Fe3+ (see Chapter 19). Studies of the subcellular distribution of aluminium in various cell lines and animal models have shown that the majority accumulates in the mitochondria, where it can interfere with calcium homeostasis. Once in the circulation, there seems little doubt that aluminium can cross the blood-brain barrier. 

Data on distribution give an indication of whether a particular tissue may be exposed to the substance or not. The extent of chemical distribution into tissues depends on the extent of plasma protein and tissue binding and this may vary among species. This is also the case for passage of chemicals into the brain, which is protected by the blood-brain barrier. 

Pregabalin does not bind to plasma proteins. The apparent volume of distribution of pregabalin following oral administration is approximately 0.5 L/kg. Pregabalin is a substrate for system L transporter, which is responsible for the transport of large amino acids across the blood-brain barrier. 

Distribution - Tinidazole is distributed into virtually all tissues and body fluids and crosses the blood-brain barrier. The apparent volume of distribution is approximately 50 L. Plasma protein binding of tinidazole is 12%. Tinidazole crosses the placental barrier and is secreted in breast milk. 

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