PROTEIN BINDING
Roselyn Aperocho-Naranjo
Faculty, College of Pharmacy
USPF
Binding of drug to proteins may:
Facilitate the distribution of drugs
Inactivate the drug by not enabling a
sufficient concentration of free drug to
develop at a receptor site
Retard the excretion of a drug
The interaction of drugs to protein may
cause:
Displacement of body hormones or
coadministered agent
Change the configuration of protein to
another structure capable of binding a
coadministered agent
Inactivates the drug biologically by forming
a drug-protein complex
Structure of Binding Site of ColonCancer Drug and Its Protein Target
Schematic showing how Erbitux takes the
place of the EGFR growth factor, thereby
inhibiting cancerous growth.
Two Important Plasma Proteins
ALBUMIN
Is the most important protein that binds to
drug molecule due to its high
concentration compared with other
proteins
It binds both acidic and basic
Constitute 5% of the total plasma
Two Important Plasma Protein
∂1-ACIDGLYCOPROTEIN
Also known as orosomucoid (∂1-globulin)
Binds to numerous drugs
Have greater affinity for basic than acidic
drugs molecules
Binds only basic and highly lipophilic drugs
Things to remember:
Many drugs bind to the same receptor site
but drugs with higher affinity will replace
those drugs with lower affinity by
competition
Only free and unbound drugs exert
therapeutic effect by interacting with
receptors
Drugs may bind to protein through:
Hydrophobic Interaction
Proposed by Kauzmann
tendency to develop of hydrophobic molecules or
parts of molecules to avoid water because they are
not readily accommodated in the H-bond structure of
water
Binding of Ca to a target protein
Drugs may bind to protein through:
Self-Association
Some drug may self dissociate to form dimers,
trimers or aggregates of larger size
Dimers or trimers - is a reaction product of two or
three identical molecules
May affect solubility, diffusion, transport, therapeutic
action of drugs
Amino Acids
A. Basic Group
Arginine
Histidine
Lysine
bind
Acidic Drugs
bin
d
Basic Drugs
Amino Acids
B. Acidic Group
Aspartic Acid
Glutamic Acid
Protein binding is determined by:
Dialysis
Ultracentrifugation
Ultrafiltration
Sephadex-gel filtration
Molecular filtration
Electrophoresis
Agar plate test
The Pharmacokinetic Importance
of Protein Binding
Drug-protein binding influences the
distribution equilibrium of the drug
Plasma proteins exert a buffer and
transport function in the distribution
process
Only free and unbound drug acts can
leave the circulatory system and diffuse
into the tissue
Disease and Protein Binding
 Protein binding will be affected by the presence of diseases
Drugs showing Decrease Extent of Protein Binding
in the following diseases:
LIVER
RENAL
Dapsone
Diazepam
Morphine
Phenytoin
Prednisolone
Quinidine
Tolbutamide
Triamterene
Barbiturates
Cardiac Glycosides
Chlordiazepoxide
Clofibrate
Diazepam
Diazoxide
Furosemide
Morphine
Phenylbutazone
Phenytoin
Salicylates
Sulfonamides
Triamterene
Disease and Protein Binding
 When drugs bind to protein, Albumin concentration is
reduced
 The exchange of proteins between plasma and
interstitial compartment (normally proceeds at a rate of
5% plasma protein per our) will be hampered.
 The diffusion of plasma the to interstitial fluid is
increased by:
 Inflammatory process
 Pregnancy
 use of oral contraceptives
 Diabetes
 Septic shock
 Pulmonary Edema
Disease and Protein Binding
The reduced albumin concentration and
binding capacity is due to:
 Change in albumin molecule
 presence of endogenous binding inhibitors such as
free fatty acids, and metabolic acidosis.
Disease and Protein Binding
Hypoalbuminemia may result in patients
with cancer, burms, cardiac failure, cystic
fibrosis, enteropathy, inflammations, liver
impairment, malabsorption, nephrotic
syndrome, renal failure, sepsis and
trauma.
Disease and Protein Binding
Pathological Conditions in which Plasma Concentration of ∂1ACIDGLYCOPROTEIN is increased
Cancer
Carcinoma, Leukemia, Lymphoma,
Malignant melanoma, myeloma
Inflammation
Crohn’s disease, Inflammatory
polyarthritis, pneumonia,
rheumatoid arthritis, ulcerative
colitis, systemic erythematosus
Myocardial Infarction
Trauma
Burns, extensive tissue damage,
surgery, transplantation
Binding of Drugs to RBC
Lipophilic molecules dissolved in the lipid
material of the RBC membrane
Anions can be attracted to and enter the
positively charged pores of RBC
Lipopilic drugs may be absorbed to rBC
membrane due to change of:
Change of shape of membrane and membrane
proteins
Membrane extension which may lead to chane of
RBC shape
Drugs absorbed in the RBC membrane
inhibits the deformity of RBC thus
becoming lodged in the capillaries
Macrophages may remove the RBC, that
results in increase free drug concentration
Binding of drugs to RBC may be
dependent on age (meperidine) and
concentration dependent (diazepam)
The RBC binding sites are:
Intracellular proteins
Hemoglobin
Carbonic anhydrase
Cell membrane
ATPase
Beneficial effects of tissue binding:
Lower tissue uptake
Lesser retention in critical organ such as
kidney, etc.
Displacement of drugs from Protein
Binding is due to:
Total amount of protein-bound drug in that
body
Extent of tissue binding structure
 Apparent volume of distribution
Displacement of Drugs from their Plasma
Protein Binding by Other Drugs given
concomitantly
Drug Displaced
By Concomitant Drug
Warfarin and other highly bound
coumarin-type anticoagulants
Clofibrate
Phenylbutazone
Ethacrynic acid
Mefenamic Acid
Nalidixic Acid
Oxyphebutazone
Chloral hydrate
Tolbutamide
Phenylbutazone
Salicylates
Sulfafurazole