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Chapter: Modern Pharmacology with Clinical Applications: Drug Absorption and Distribution

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Binding of Drugs to Plasma Proteins

Most drugs found in the vascular compartment are bound reversibly with one or more of the macromole-cules in plasma.

BINDING OF DRUGS TO PLASMA PROTEINS

Most drugs found in the vascular compartment are bound reversibly with one or more of the macromole-cules in plasma. Although some drugs simply dissolve in plasma water, most are associated with plasma components such as albumin, globulins, transferrin, ceruloplas-min, glycoproteins, and - and -lipoproteins. 

While many acidic drugs bind principally to albumin, basic drugs frequently bind to other plasma proteins, such as lipoproteins and 1-acid glycoprotein ( 1-AGP), in ad-dition to albumin. The extent of this binding will influ-ence the drug’s distribution and rate of elimination be-cause only the unbound drug can diffuse through the capillary wall, produce its systemic effects, be metabo-lized, and be excreted.

Drugs ordinarily bind to protein in a reversible fash-ion and in dynamic equilibrium, according to the law of mass action. Since only the unbound (or free) drug dif-fuses through the capillary walls, extensive binding may decrease the intensity of drug action. The magnitude of this decrease is directly proportional to the fraction of drug bound to plasma protein. At low drug concentra-tions, the stronger the affinity between the drug and protein, the smaller the fraction that is free. As drug dosage increases, eventually the binding capacity of the protein becomes saturated and any additional drug will remain unbound.

The binding of a drug to plasma proteins will de-crease its effective plasma to tissue concentration gradi-ent, that is, the force that drives the drug out of the cir-culation, thereby slowing the rate of transfer across the capillary. As the free drug leaves the circulation, the protein–drug complex begins to dissociate and more free drug becomes available for diffusion. Thus, binding does not prevent the drug from reaching its site of ac-tion but only retards the rate at which this occurs. Extensive plasma protein binding may prolong drug availability and duration of action.

Protein binding also plays a role in the distribution of drugs and thus the volume of distribution. Drugs that are highly bound to plasma proteins may distribute less widely because they remain trapped in the peripheral vas-culature, since the plasma proteins themselves cannot tra- verse into the extravascular space. However, if the affinity of a drug for tissues (e.g., fat, muscle) is greater than the affinity for plasma proteins, widespread distribution can occur despite a high degree of plasma protein binding.

Albumin

Of the plasma proteins, the most important contributor to drug binding is albumin. Although albumin has a net negative charge at serum pH, it can interact with both positive and negative charges on drugs. Many highly al-bumin-bound drugs are poorly soluble in water, and for such drugs, binding to hydrophobic sites on albumin is often important. In general, only one or two molecules of an acidic drug are bound per albumin molecule, whereas basic, positively charged drugs are more weakly bound to a larger number of binding sites.

The binding of drugs to plasma proteins is usually nonspecific; that is, many drugs may interact with the same binding site. A drug with a higher affinity may dis-place a drug with weaker affinity. Increases in the non–protein-bound drug fraction (i.e., free drug) can theoretically result in an increase in the drug’s intensity of pharmacological response, side effects, and potential toxicity. However, in practice, changes in protein bind-ing result in clinically significant effects for only a lim-ited number of drugs.

Some disease states (e.g., hyperalbuminemia, hy-poalbuminemia, uremia, hyperbilirubinemia) have been associated with changes in plasma protein binding of drugs. For example, in uremic patients the plasma pro-tein binding of certain acidic drugs (e.g., penicillin, sul-fonamides, salicylates, and barbiturates) is reduced.

Lipoproteins

Drugs that bind to lipoproteins do so by dissolving in the lipid portion of the lipoprotein core. The bindingcapacity of individual lipoproteins generally depends on their lipid content. It is also possible that the lipid and protein fractions cooperate in the binding process, the drug first binding to a number of sites on the protein moiety and then dissolving in the lipid phase.

α1-Acid Glycoprotein

The importance of 1-AGP as a determinant of the plasma protein binding of basic drugs, including the psychotherapeutic drugs chlorpromazine, imipramine, spiroperidol, and nortriptyline, is becoming apparent. There is evidence of increased plasma 1-AGP levels in certain physiological and pathological conditions, such as injury, stress, surgery, trauma, rheumatoid arthritis, and celiac disease.

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