Proteins binding sites and

Most drugs are carried by the circulation from their site of administration to their sites of action and elimination. Competition for protein binding sites and other factors have been described in Chapter 2, and some relevant examples are given in Table 18.1. 

Proximal tubular secretion is an energy-dependent active-transport mechanism. Specific high-affinity proteins in the proximal tubule transport drugs into the tubule for elimination via the urine. These proteins can also remove acidic and basic drugs from plasma protein-binding sites and transport them into the tubule. Since it is carrier-mediated, this mechanism is a saturable system. Therefore, other drugs may also compete for transport where similar carriers are employed. 

A recently proposed variant to this method is the use of a spin labelled first ligand, that binds to the main protein binding site, and in this way the procedure is applied only for the screening of a second ligand [143, 144], The presence of a spin label induces a very fast T2 relaxation on ligands that bind nearby the first fragment, and the effect on the line shape is therefore enhanced. 

METHOTREXATE SULFAMETHOXAZOLE/ TRIMETHOPRIM t plasma concentrations of methotrexate and risk of toxic effects of methotrexate, e.g. myelosuppression, liver cirrhosis, pulmonary toxicity Sulfamethoxazole displaces methotrexate from plasma protein-binding sites and also 1 renal elimination of methotrexate. Trimethoprim inhibits dihydrofolate reductase, which leads to additive toxic effects of methotrexate Avoid concurrent use. If concurrent use is necessary, monitor clinically and biochemically for blood dyscrasias and liver, renal and pulmonary toxicity... 

RIFAMPICIN ANTIPROTOZOALS -LEVAMISOLE 1 therapeutic efficacy of rifampicin Levamisole displaces rifampicin from protein-binding sites and T free fraction nearly three times and thus T clearance of rifampicin Avoid co-administration if possible... 

In the last few years, a number of publications have demonstrated that the GRID/PCA or GRID/CPCA methods can be successfully applied to characterize the structural differences between protein binding sites, and to identify differences in the protein-ligand interactions as well as the regions on the target enzymes which mediate highly selective interactions [4—17]. 

For a displacement interaction to become clinically important, a second mechanism usually operates sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules the result is serious methotrexate toxicity. 

Phenylbutazone Phenytoin Valproate Risk of toxicity, particularly with phenytoin altered relation between total concentration and effect Displacement from plasma protein binding sites and inhibition of metabolism of the affected drugs... 

The pharmacokinetic interaction of phenytoin with valproate is complicated (78-80). Initially, the total serum phenytoin concentration falls, because valproate displaces phenytoin from protein binding sites and so the unbound fraction increases, with a consequent increase in clearance. Because of the change in unbound fraction the total plasma concentration effect curve is shifted to the left, and a lower total concentration is as effective as the total phenytoin concentration was in the absence of valproate. However, valproate also inhibits the metabolism of phenytoin and so the serum phenytoin concentration then starts to rise and there is a risk of toxicity. 

INR = initiator region. The shapes above the bar symbolize additional protein binding sites and the arrow indicates the transcription start site. 

Probing of the phosphates is informative for localisation of protein binding sites and in particular for determination of the groove that interacts with the protein. Unfortunately, phosphates are rather inert and ethylnitrosurea (ENU) which has been used as a probe reacts under very harsh conditions where most RNA-protein complexes will dissociate. However, when in vitro transcribed... 

Ma B, Elkayam T, Wolfson H, Nussinov R (2003) Protein-protein interactions structurally conserved residues distinguish between protein binding sites and exposed protein surfaces. Proc Natl Acad Sci USA 100 5772-5777... 

Drugs can compete for the same protein binding sites and this is a form of drug interaction. A well-known and important example is that of warfarin and aspirin. Warfarin is an anticoagulant, which binds extensively to plasma proteins, and this is taken into account when dosages are worked out. Aspirin taken with warfarin competes for the same... 

Active transport does not depend on concentration gradients and can overcome plasma protein binding. As the free drug is transported, more of the drug dissociates from the protein binding site and can be eliminated. 

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