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.