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PROTEIN BINDING
Interaction of Drug with Tissue Protein
Interaction of Drug with Plasma Protein
Tissue Protein Binding
• Drug may bind reversibly with proteins
• Some drugs are highly bound to tissue proteins
• Free drugs penetrate cell membranes, distributing
into various tissues including those tissues
involved in drug elimination (kidney, liver)
• Active renal secretion – carrier mediated system,
may have a greater affinity for free drug molecul
compared to plasma protein
• In this case, active renal drug excretion allows for
rapid drug excretion despite drug protein binding
• Some models: the drug distributes from the plasma water
into extracellular tissue fluid, where the drug binds to
extravascular proteins, resulting in a relatively larger VD
due to extracellular protein binding
• Drugs with lower distribution to the extracellular water are
more extensively distributed inside the tissues (Protein
binding to tissue) and tend to have a large apparent
volume of distribution
• Binding of drugs by tissue may necessitate a larger initial
bolus to achieve the desired effect (the concentration in
receptor large enough to give pharmacological effect)
• Large depots of drug in tissue may necessitate a longer
period of time for drug to be removed from the body
• An excessively high VD (>body volume of 70 L) is due
mostly to special tissue storage, tissue protein binding,
carrier, or efflux system which removes drug from the
plasma fluid : Digoxin, is bound to myocardial
membrane
• The high tissue binding is responsible for the large
steady state volume of distribution
• The greater drug affinity also results in longer
distribution α half-life in spite of the heart’s great
vascular blood perfusion
• Imipramin is highly protein bound and concentrated in
plasma, yet its favorable tissue partition and binding
accounts for a large volume of distribution.
• TCA (Tri Cyclic Antidepressants– large volume of
distribution due to tissue (CNS) penetrating and
binding
• The accumulation of drug into tissues is
dependent on:- the blood flow
- the affinity of the drug for the tissue
• The drug concentration in a tissue with low
capacity equilibrates rapidly with the
plasma drug concentration and then
declines rapidly as the drug is eliminated
• Drugs with high tissue affinity tend to
accumulate or concentrate in the tissue
• Drugs may accumulate in tissue by binding
to proteins or other macromolecules in a
tissue
• Drug accumulate in tissue - binding to protein
tissue: Digoxin – highly binding to protein in
cardiac tissue – leading in a large volume of
distribution ( 440 L / 70 kg) and long t1/2 (40 hrs)
• Some drugs complex with melanin in the skin and
eye after long term administration of high doses of
phenothiazine to chronic schizophrenic patients
• Tetracycline – forms an insoluble chelate with
calcium on teeth and bones
• Amphetamin (phenilethylamine structure) ≈
norepinephrine, is actively transported into and
accumulated in adrenergic tissue (a specific uptake
system for catecholamin/ norepinephrine)
Plasma protein Binding
• Many drugs bind to circulating plasma
proteins to form a drug-macromolecule
complex or drug-protein binding by a
reversible or irreversible process. Since
these proteins are large, bound drugs cannot
pass out of vascular space – thus plasma
protein binding has the effect of restricting
the distribution of drugs
• As plasma protein binding increases, the
extent of distribution decreases
Irreversible drug protein binding
• A result of the chemical activation of the drug,
which then attaches strongly to the
protein/macromolecule by covalent bonding
• Accounts for certain types of drug toxicity occurred
over a long time period – chemical carcinogenesis
• Within relatively short time period – drugs that form
reactive chemical intermediates : hepatotoxic of
high dose of paracetamol is due to the formation of
reactive metabolite intermediates that interact with
liver proteins
Reversible drug-protein binding
• Large complex that cannot easily transverse cell or
possibly even capillary membranes and therefore
has a restricted distribution
• Pharmacology inactive
• Free/unbound drug crosses cell membranes and is
therapeutically active
• Studies is done in vitro using albumin purified
protein including equilibrium dialysis and
ultrafiltration using a semipermeable membrane
that separates the protein and protein-bound drug
from the free/unbound drug, and total protein may
be determined, with advantage and disadvantage
• Drugs may bind to various macromolecular
components in the blood including albumin, α1acid glycoprotein, lipoproteins, immunoglobulins
(IgG), and erythrocytes (RBC)
• Effect of protein binding on the VD
• Relation of plasma drug-protein binding to
distribution and elimination
• Relationship between VD and Drug elimination
half life
• Elimination of Protein-bound drug: Restrictive
versus Nonrestrictive Elimination
Methods for Studying Drug-Protein
Binding
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Equilibrium Dialysis
Dynamic dialysis
Diafiltration
Ultrafiltration
Gel Chromatography
Spectrophotometry
Electrophoresis
Optical Rotary Dispersion Circulatory dichroism
Kinetics of Protein Binding