Binding to Plasma Proteins
Having entered the blood, drugs may
bind to the protein molecules that are
present in abundance, resulting in the
formation of drug-protein complexes.
Protein binding involves primarily albumin
and, to a lesser extent, !-globulins
and acidic glycoproteins. Other
plasma proteins (e.g., transcortin, transferrin,
thyroxin-binding globulin) serve
specialized functions in connection
with specific substances. The degree of
binding is governed by the concentration
of the reactants and the affinity of a
drug for a given protein. Albumin concentration
in plasma amounts to
4.6 g/100 mL or O.6 mM, and thus provides
a very high binding capacity (two
sites per molecule). As a rule, drugs exhibit
much lower affinity (KD approx.
10–5 –10–3 M) for plasma proteins than
for their specific binding sites (receptors).
In the range of therapeutically relevant
concentrations, protein binding of
most drugs increases linearly with concentration
(exceptions: salicylate and
certain sulfonamides).
The albumin molecule has different
binding sites for anionic and cationic ligands,
but van der Waals’ forces also
contribute. The extent of binding
correlates with drug hydrophobicity
(repulsion of drug by water).
Binding to plasma proteins is instantaneous
and reversible, i.e., any
change in the concentration of unbound
drug is immediately followed by a corresponding
change in the concentration
of bound drug. Protein binding is of
great importance, because it is the concentration
of free drug that determines
the intensity of the effect. At an identical
total plasma concentration (say, 100
ng/mL) the effective concentration will
be 90 ng/mL for a drug 10 % bound to
protein, but 1 ng/mL for a drug 99 %
bound to protein. The reduction in concentration
of free drug resulting from
protein binding affects not only the intensity
of the effect but also biotransformation
(e.g., in the liver) and elimination
in the kidney, because only free
drug will enter hepatic sites of metabolism
or undergo glomerular filtration.
When concentrations of free drug fall,
drug is resupplied from binding sites on
plasma proteins. Binding to plasma protein
is equivalent to a depot in prolonging
the duration of the effect by retarding
elimination, whereas the intensity
of the effect is reduced. If two substances
have affinity for the same binding site
on the albumin molecule, they may
compete for that site. One drug may displace
another from its binding site and
thereby elevate the free (effective) concentration
of the displaced drug (a form
of drug interaction). Elevation of the
free concentration of the displaced drug
means increased effectiveness and accelerated
elimination.
A decrease in the concentration of
albumin (liver disease, nephrotic syndrome,
poor general condition) leads to
altered pharmacokinetics of drugs that
are highly bound to albumin.
Plasma protein-bound drugs that
are substrates for transport carriers can
be cleared from blood at great velocity,
e.g., p-aminohippurate by the renal tubule
and sulfobromophthalein by the
liver. Clearance rates of these substances
can be used to determine renal or hepatic
blood flow.
Having entered the blood, drugs may
bind to the protein molecules that are
present in abundance, resulting in the
formation of drug-protein complexes.
Protein binding involves primarily albumin
and, to a lesser extent, !-globulins
and acidic glycoproteins. Other
plasma proteins (e.g., transcortin, transferrin,
thyroxin-binding globulin) serve
specialized functions in connection
with specific substances. The degree of
binding is governed by the concentration
of the reactants and the affinity of a
drug for a given protein. Albumin concentration
in plasma amounts to
4.6 g/100 mL or O.6 mM, and thus provides
a very high binding capacity (two
sites per molecule). As a rule, drugs exhibit
much lower affinity (KD approx.
10–5 –10–3 M) for plasma proteins than
for their specific binding sites (receptors).
In the range of therapeutically relevant
concentrations, protein binding of
most drugs increases linearly with concentration
(exceptions: salicylate and
certain sulfonamides).
The albumin molecule has different
binding sites for anionic and cationic ligands,
but van der Waals’ forces also
contribute. The extent of binding
correlates with drug hydrophobicity
(repulsion of drug by water).
Binding to plasma proteins is instantaneous
and reversible, i.e., any
change in the concentration of unbound
drug is immediately followed by a corresponding
change in the concentration
of bound drug. Protein binding is of
great importance, because it is the concentration
of free drug that determines
the intensity of the effect. At an identical
total plasma concentration (say, 100
ng/mL) the effective concentration will
be 90 ng/mL for a drug 10 % bound to
protein, but 1 ng/mL for a drug 99 %
bound to protein. The reduction in concentration
of free drug resulting from
protein binding affects not only the intensity
of the effect but also biotransformation
(e.g., in the liver) and elimination
in the kidney, because only free
drug will enter hepatic sites of metabolism
or undergo glomerular filtration.
When concentrations of free drug fall,
drug is resupplied from binding sites on
plasma proteins. Binding to plasma protein
is equivalent to a depot in prolonging
the duration of the effect by retarding
elimination, whereas the intensity
of the effect is reduced. If two substances
have affinity for the same binding site
on the albumin molecule, they may
compete for that site. One drug may displace
another from its binding site and
thereby elevate the free (effective) concentration
of the displaced drug (a form
of drug interaction). Elevation of the
free concentration of the displaced drug
means increased effectiveness and accelerated
elimination.
A decrease in the concentration of
albumin (liver disease, nephrotic syndrome,
poor general condition) leads to
altered pharmacokinetics of drugs that
are highly bound to albumin.
Plasma protein-bound drugs that
are substrates for transport carriers can
be cleared from blood at great velocity,
e.g., p-aminohippurate by the renal tubule
and sulfobromophthalein by the
liver. Clearance rates of these substances
can be used to determine renal or hepatic
blood flow.
