Tissue affinity

Table 1.1 shows the preferential binding of chlorphentermine to phosphatidylcholine-containing membranes, the phospholipid with overall acidic charge. These systems predict the actual affinity of the compound for the membrane, rather than its ability to cross the membrane. Membrane affinity, and hence tissue affinity, is particularly important in the persistence of drugs within the body, a topic which wiU be covered in Section 4.2. 

The volume of distribution of a drug molecule is, as described previously, a theoretical number that assumes the drug is at equal concentration in the tissue and in the circulation and represents what volume (or mass) of tissue is required to give that concentration. Volume of distribution, therefore, provides a term that partially reflects tissue affinity. However, it is important to remember that affinity may vary between different tissues and a moderate volume of distribution may reflect moderate concentrations in many tissues or high concentrations in a few. For an illustration of... 

A further property which is of central importance in diffusion is the tissue-binding capacity (or affinity) of a drug. Drugs that are highly lipid-soluble and protein-bound, such as bupivacaine and ropivacaine, are extensively bound to tissue. This limits the rate at which they are transferred from their intracellular sites of action to the vascular compartment. When tissue affinity is great the local anaesthetic effect is prolonged. 

According to Lee et al. (2010), the peptide Gly-Asp-Leu-Gly-Lys-Thr-Thr-Thr-Val-Ser-Asn-Trp-Ser-Pro-Pro-Lys-Try-Lys-Asp-Thr-Pro, derived from big-eye tuna frame protein hydrolysate, showed a strong suppressive effect on the systolic blood pressure of SHRs, while its antihypertensive activity was similar to that of captopril, a commercially available antihypertensive drug. Further, they reported no side effects after the administration of this antihypertensive peptide to rats. In addition, these marine antihypertensive peptides exhibit stronger antihypertensive activity in vivo than in vitro. The exact mechanisms underlying this phenomenon have yet to be identified however, it was suggested that bioactive peptides have a higher tissue affinity and are eliminated more slowly than captopril (Fujita and Yoshikawa, 1999). 

This physiological approach to defining volume is useful to help explain which drug might be more likely to reside outside the blood based on tissue affinity (fup/ fut), but does not readily lend itself to a calculation because of the difficulty in determining either free or total concentrations in the tissue. A simpler mathematical expression of Vss would be one related to equilibrium conditions achieved with a continuous intravenous (IV) infusion (R0) at steady-state where ... 

Both natural polymers such as polysaccharides and synthetic polymers such as polylysine, polyglutamic acid, polyphosphazenes, copolymers of vinylpyrrolidone, copolymers of 2-hydroxypropylmeth-acrylamide, and etc. have been used as drug carriers. The structure of these polymers can be modified by the incorporation of hydro-phobic units, sugar residues, or sulfonyl groups to achieve a specific tissue affinity. 

The model was developed from several data sets in which rats were dosed with chromium(VI) or chromium(III) intravenously, orally, or by intratracheal instillation, because depending on route of administration, different distribution and excretion patterns occur. In cases where parameters were not available (absorption rates, tissue affinity, biotransformation), estimates were obtained by fitting. This was done by duplicating the initial conditions of published experiments in the model, varying the unknown parameters and comparing the results of the simulation to the reported results. Tissue affinity constants were estimated using reported chromium levels in tissues at various times after exposure. 

Muller, R. H., and Heinemann, S. (1989), Surface modeling of microparticles as parenteral systems with high tissue affinity, in Bioadhesion-Possibilities and Future Trends, Wissenschaftliche Verlagsgesellschaft, Stuttgart, pp. 202-214. 

The effects of drought, i.e., the quantitative properties of water in fresh and dry leaves of durum wheat were tested by the relation between the water status and the properties of bound water (BW) with different strengths to ionic, polar, or hydrophobic sites of macromolecules [56]. An increase in tissue affinity for strongly bound water implied a simultaneous increase in the affinity for weakly bound water. The qualitative properties of bound water may be particularly important for drought adaptation in durum wheat, which is associated with solute potential plots of differential energies of water sorption (Figure 4). 

Because of the lipase deficiency, fat-soluble vitamin (A, D, E, and K) deficiencies may occur. Whether lipase activity or bile acids (e.g., in micelle formation) are involved in fat-soluble vitamin absorption with steatorrhea is unclear. Vitamin and zinc deficiencies also may occur as aresult of pancreatic enzyme deficiency. Although pancreatic involvement is predominantly exocrine in nature, insulin deficiency with glucose intolerance also occurs in CF patients, especially as they advance in age. Carbohydrate intolerance is characterized by low insulin concentrations and enhanced peripheral sensitivity to insulin but not by the presence of islet cell or anti-insulin antibodies. Carbohydrate intolerance in CF is not usually associated with the ketosis as commonly occurs in type 1 diabetes. This complication involves an increase in the number of insulin receptors with decreased affinity for insulin. Despite a concomitant increase in tissue affinity for insulin, 8% of CF children over 12 years of age require insulin therapy. 

New macrolides share the high tissue affinity of erythromycin, but marked variations are seen in the pharmacokinetic parameters such as the... 

The concentration of a compound In the plasma Is Important since It generally reflects the level at the site of action. Once a compound has entered the bloodstream It may be excreted, stored, or metabolized its metabolites may be excreted or stored or the compound or its metabolites may reach target organs and interact with, or bind to, cellular components. Parameters that influence the distribution of a compound from the blood to the tissues of the body include blood flow, membrane barriers, ion trapping, plasma binding, and tissue affinity most are well characterized and can be readily predicted. 

Veng-Pedersen, P. and Gillespie, W. R., Single pass mean residence time in peripheral tissues a distribution parameter intrinsic to the tissue affinity of a drug, J. Pharm. Sci., 75 1119-1126, 1986. 

Distribution Extracellular, low tissue affinity Extracellular, low tissue affinity Low tissue affinity... 

Rascio, A., Russo, M., Platani, C., Ronga, G., and Di Fonzo, N. 1999. Mutants of durum wheat with alterations in tissue affinity for strongly bound water. Plant Sci. 144 29-34. 

---