Protein Binding – Medicinal Chemistry

PROTEIN BINDING

Contents

• Protein binding

• Effects of protein binding

• Types of plasma proteins

• Determination of protein binding

• Pharmacokinetic Importance of protein binding

• Disease and protein binding

Intended
learning outcomes

At the end of this
lecture, student will be able to:

• Explain the importance of protein binding of drug
molecules on biological action.

Binding of
drug to proteins may:

• Facilitate the distribution of drugs.

• Inactivate the drug by not enabling a sufficient concentration
at a receptor site

• Retard the excretion of a drug.

The
interaction of drugs to protein may cause:

• Displacement of body hormones or co-administered agent

• Change the configuration of protein to another structure
capable of binding a co-administered agent

• Inactivates the drug biologically by forming a drug-
protein complex

Two Important Plasma Proteins

1. ALBUMIN

2. ACIDGLYCOPROTEIN

ALBUMIN

• 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 drugs.

• Constitutes 5% of the total plasma.

∂1-ACIDGLYCOPROTEIN

• Also known as orosomucoid (∂1-globulin)

• Binds to numerous drugs

• Have greater affinity for basic than acidic drugs
molecules

• Binds mostly 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:

• 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

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               

Salicylates

Cardiac Glycosides   

Sulfonamides

Chlordiazepoxide

Triamterene

Clofibrate

Diazepam

Diazoxide

Furosemide

Morphine

Phenylbutazone

Phenytoin

• 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 to the interstitial fluid is
increased by:

• Inflammatory process

• Pregnancy

• Use of oral contraceptives

• Diabetes

• Septic shock

• Pulmonary Edema

• 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.

• Hypoalbuminemia may result in patients with cancer, burns,
cardiac failure, cystic fibrosis, enteropathy, inflammations, liver impairment,
malabsorption, nephrotic syndrome, renal failure, sepsis and trauma.

Pathological
Conditions in which Plasma Concentration ∂1 – ACIDGLYCOPROTEIN 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

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

SUMMARY

• 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 and constitute 5% of the
total plasma

• ∂1-acidglycoprotein also known as orosomucoid
(∂1-globulin) and binds to numerous drugs

• Have greater affinity for basic than acidic drugs
molecules Binds only basic and highly lipophilic drugs

• Effects of protein binding and its pharmacokinetic importance
is studied.

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