Tissue-binding interactions

Clearly, the mechanistic contributors to the extent of plasma and tissue binding are numerous, and the VD term represents a simplistic picture of potentially hundreds, maybe thousands, of individual tissue binding interactions. Despite this possible complexity, there may be a few individual types of tissue binding that are mostly responsible for tissue partitioning, and as described elsewhere in this chapter, this phenomena may be more related to non-specific interactions that are a function of gross physicochemical properties of the drug than specific binding interactions. 

Hemoglobins bind four molecules of Oj per tetramer, one per heme. A molecule of Oj binds to a hemoglobin tetramer more readily if other Oj molecules are already bound (Figure 6-4). Termed cooperative binding, this phenomenon permits hemoglobin to maximize both the quantity of O2 loaded at the PO2 of the lungs and the quantity of O2 released at the PO2 of the peripheral tissues. Gooperative interactions, an exclusive property of multimeric proteins, are critically important to aerobic life. 

Nonspecific background problems are the result of primary or secondary antibody binding to the tissue through interactions that do not involve the antigen combin-... 

Toxicity is most likely in tissues that interact with the drug. For example, gentamicin is polycationic and binds to anionic phospholipids in the cell membranes of renal proximal tubular cells, where it inhibits phospholipases and damages intracellular organelles. 

MacGregor, J. T. and Clarkson, T. W. (1974). Distribution, tissue binding and toxicity of mercurials. In "Protein-Metal Interactions", (M. Friedman, ed.), Plenum Press, New York, pp. 463-503. 

E-cadherin is unique in that it not only, like other cadherin family members, mediates homophilic adhesion to establish and maintain cellcell contacts, it also serves as a counter-receptor for integrins Oe/37 (Cepek et al, 1994) and (Whittard et al, 2002) in heterophilic adhesion. In fact, the interaction between E-cadherin on mucosal epithelial cells and Oe/S on intraepithelial lymphocytes has been the best characterized tissue-specific interaction for lymphocyte retention. Although structure of binding domains between E-cadherin and is not available, mutagenesis... 

Chapter 15, this leads to interactions between compounds that compete for the same binding sites on serum albumin. However, coadministered compounds also may compete for tissue binding sites, as demonstrated by the interaction between quinidine and digoxin (11). The extent of drug distribution across a membrane will depend on the relative affinity of competing compounds for both plasma and tissue binding sites. 

Interaction with digoxin (by displacement from tissue binding sites and interference with its... 

The extent and degree of interactions between chiral macromolecules of the body and stereoisomers is a source of observable differences in isomeric drug distribution. Stereoselectivity in drug distribution may occur when tissue or protein binding or uptake is associated with structurally specific receptor, protein, or enzyme binding. Since only unbound or free drug is susceptible to elimination and distribution to receptors and other tissues and fluids, differences in the protein and tissue binding of stereoisomers are reflected in their overall pharmacokinetic profiles. 

Identical chemical and physical properties of enantiomers represent a potential source for enantiomer-enantiomer interactions at both pharmacokinetic and pharmacodynamic levels. Whether by competition for plasma- or tissue-binding sites or for drug-metabolizing enzymes, enantiomers may exhibit changes in pharmacokinetics when administered as a racemate compared to individual stereoisomers. The enantiomers of disopyramide exhibit similar clearance and volumes of distribution when given separately. " However, when administered as the racemate, the 5... 

Cell adhesion molecules (CAMs) are transmembrane glycoproteins that act at the cell surface to mediate specific binding interactions with other cell adhesion molecules on adjacent cells or with proteins in the extracellular matrix. They are responsible for the adhesion of various leukocytes with each other, with extracellular matrix and with other cell types. Several classes of molecules capable of mediating adhesion include selectins, integrins, cadherins, and immunoglobulin superfamily members [263-265]. Multiple members from every major family of cell adhesion molecules have been implicated in the development, maintenance, or repair of renal tissues... 

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