Plasma Protein Andtissue Binding

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Many natural substances circulate around the body partly free in plasma water and partly bound to plasma proteins; these include Cortisol, thyroxine, iron, copper and, in hepatic or renal failure, byproducts of physiological intermediary metabolism. Drugs, too, circulate in the protein-bound and free states, and the significance is that the free fraction is pharmacologically active whereas the protein-bound component is a reservoir of drug that is inactive because of this binding. Free and bound fractions are in equilibrium and free drug removed from the plasma by metabolism, dialysis or excretion is replaced by drug released from the bound fraction.

Albumin is the main binding protein for many natural substances and drugs. Its complex structure has a net negative charge at blood pH and a high capacity but low (weak) affinity for many basic drugs, i.e. a lot is bound but it is readily released. Two particular sites on the albumin molecule bind acidic drugs with high affinity (strongly) but these sites have low capacity. Saturation of binding sites on plasma proteins in general is unlikely in the doses in which most drugs are used.

Other binding proteins in the blood include lipoprotein and c^-acid glycoprotein, both of which carry basic drugs such as quinidine, chlorpromazine and imipramine. Such binding may have implications

17 Litres per kg are commonly used, but give a less vivid image of the implication of the term 'apparent', e.g. chloroquine.

for therapeutic drug monitoring according to plasma concentration. Thyroxine and sex hormones are bound in the plasma to specific globulins.

Disease may modify protein binding of drugs to an extent that is clinically relevant as Table 7.3 shows. In chronic renal failure, hypoalbuminaemia and retention of products of metabolism that compete for binding sites on protein are both responsible for the decrease in protein binding of drugs. Most affected are acidic drugs that are highly protein bound, e.g. phenytoin, and special care is needed when initiating and modifying the dose of such drugs for patients with renal failure (see also Prescribing in renal disease, p. 541).

Chronic liver disease also leads to hypoalbuminaemia and increase of endogenous substances such as bilirubin that may compete for binding sites on protein. Drugs that are normally extensively protein bound should be used with special caution, for increased free concentration of diazepam, tolbutamide and phenytoin have been demonstrated in patients with this condition (see also Prescribing in liver disease, p. 652).

The free, unbound and therefore pharmacologically active percentages of some drugs are listed in Table 7.3 to illustrate the range and, in some cases, the changes caused by disease.

Drugs may interact competitively at plasma protein binding sites as is discussed on page 131.

Tissue binding. Some drugs distribute readily to regions of the body other than plasma, as a glance

TABLE 7.3 Examples of plasma protein binding of

drugs and effects of disease


% unbound (free)


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