Serum binding

SCHEME 7.5 Effect of protein binding upon elimination 

Advanced treatments of pharmacokinetics introduce mathematical relationships between Vd and serum binding. Serum binding is often noted by variables such as /u (fraction unbound). Distinctions between drug that is free in the blood (/ub) and tissue (/u ) are common. 

FIGURE 7.8 Drugs that competitively bind serum albumin 

It is possible to rationally design a compound with minimized serum binding. The following Case Study demonstrates this idea. 

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Methyl paraoxon may also be made unavailable by binding to noncritical tissue and plasma constituents (Benke and Murphy 1975), including cholinesterase (Parkinson 1996). In addition, the parent compound is bound to albumin, in serum, as discussed previously in Section 3.4.2.4, but this binding does not appear to limit the availability of methyl parathion to the tissues, indicating that it is reversible. Tissue binding appears to be more important than serum binding (Braeckman et al. 1980, 1983). 

Table 42-8. Approximate affinities of steroids for serum-binding proteins.

The presence of serum-binding proteins. Some biopharmaceuticals (including insulin-like growth factor (IGF), GH and certain cytokines) are notable in that the blood contains proteins that specifically bind them. Such binding proteins can function naturally as transporters or activators, and binding can affect characteristics such as serum elimination rates. 

I. S. Bennett, N. J. P. Broom, K. Coleman, S. Coulton, P. D. Edwards, I. Francois, D. R. J. Griffin, N. F. Osborne, P. M. Woodall, 6-(Substituted Methylene) Penems, Potent Broad Spectrum Inhibitors of Bacterial /3-Lactamase. IV. Kidney Stability, Serum Binding and Additional Biological Evaluation of Racemic Derivatives , J. Antibiot. 1991,44, 338-343. 

This leads to two incorrect assumptions that (i) the absence of human serum represents a protein- or serum-free potency measure (despite 10% fetal calf serum being a component) (ii) the presence of 50% human serum (and 10% PCS) representing the full effect of serum binding [16]. 

Serum binding protein with bound hormone I... 

Hormone (H), carried to the target tissue on serum binding proteins, diffuses across the plasma membrane and binds to its specific receptor protein (Rec) in the nucleus. 

Colostral Lipase. Driessen (1976) identified a lipase in bovine colostrum which is stable at pH 4.6, is bound to casein micelles, but is situated in the milk serum. Binding to heparin-Sepharose was weak, and... 

Although serum binding slows elimination, all of a drug in the body is still subject to elimination. Protein binding is a dynamic equilibrium. As the concentration of unbound drug is reduced by elimination, bound drug will release to maintain a constant bound-to-unbound drug ratio (Scheme 7.5). 

FIGURE 7.9 Designing a drug to minimize serum binding... 

Fatemi SJA, Kadir FHA, Moore GR. 1991. Aluminum transport in blood serum - binding of aluminum by human transferrin in the presence of human albumin and citrate. Biochem J 280 527-532. 

S. Glasson, R. Zini, and J. P. Tillement, Multiple human serum binding of two... 

Pharmacological properties (serum binding, distribution, clearance, half-life, etc.) Synthetic accessibility, simplicity, patentability Many of these properties may be influenced by the nonspecific affinity of the compound for host proteins however, these properties are not generally predictable from target choice at this time. Size, shape, and amino acid composition of the inhibitorbinding site may influence the chemical classes of inhibitors, as well as the achievable selectivity. 

Disposable 24-well BD Gentest Serum Binding System with 24 well dialysis insert, containing individual Spectrapor 2 membranes and 24 well BD Falcon Microplate (BD Biosciences Bedford MA USA Cat. No 453700)... 

Such WPP can be used to enhance product textures by making use of the functional properties of WPP, such as serum binding capacity (Figure 19.12), as long as their size does not exceed approximately 20 pm to prevent undesired mouth feel sensations. 

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