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.
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.
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.
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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