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Protein binding of drugs

Protein binding describes the ability of drugs to form reversible or irreversible bonds with plasma and tissue proteins like albumin and alpha-1-acid glycoprotein. Only the unbound fraction of a drug interacts with receptors and is available to be metabolized or excreted, so protein binding significantly impacts a drug's effects, distribution, and clearance from the body. The degree of binding is determined by properties of both the drug and binding proteins, and can be altered through drug interactions that displace one drug from its binding sites.

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Protein Binding of Drugs Many drugs interact with plasma or tissue proteins or with other macromolecules, such as melanin and DNA, to form a drug– macromolecule complex. The formation of a drug protein complex is often named drug–protein binding AFROZ KHAN
• The rate of distribution of drug from blood to tissue depend on the blood volume of organs. The more blood volume the organ has, the faster the amount of drug diffused. Then there is a redistribution in some organs. e.g. Thiopental is lipophilic drug, and it diffuses into brain more quickly, then, redistribute to the fat and other tissues.
• The concentration of drug at target organ should be measured through the concentration of plasma. So the effect of the drug may be estimated at target organ.
• Protein binding describes the ability of proteins to form bonds with other substances, and most commonly refers to the bonding of drugs to these molecules in blood plasma, red blood cells, other components of the blood, and to tissue membranes.
Biological relevance of drug binding • The binding of drug to plasma (and tissue) proteins is a major determinant of drug disposition (distribution) • Binding has a very important effect on drug dynamics since only the free (unbound) drug interacts with receptors
Binding of Drugs • The proteins commonly involved in binding with drugs are albumin, lipoproteins, and a1-acid-glycoprotein (AGP). Acidic and neutral compounds will tend to bond with albumin, which is basic, while basic substances will primarily bind to the acidic AGP molecule.
• The bound drug is kept in the blood stream while the unbound component may be metabolized or excreted, making it the active part. • So, if a drug is 95% bound to a binding protein and 5% is free, that means that 5% is active in the system and causing pharmacological effects.
• Drug–protein binding may be a reversible or an irreversible process. • Irreversible drug–protein binding is usually a result of chemical activation of the drug, which then attaches strongly to the protein or macromolecule by covalent chemical bonding. • Irreversible drug binding accounts for certain types of drug toxicity that may occur over a long time period
• For example, the hepatotoxicity of high doses of acetaminophen is due to the formation of reactive metabolite intermediates that interact with liver proteins.
• Reversible drug–protein binding implies that the drug binds the protein with weaker chemical bonds, such as hydrogen bonds or vander Waals forces.
• A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Common blood proteins that drugs bind to are human serum albumin, lipoprotein, glycoprotein, α, β‚ and γ globulins.
• A drug in blood exists in two forms: bound and unbound • It is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be metabolized and or excreted. • For example, the "fraction bound" of the anticoagulant warfarin is 97%. This means that of the amount of warfarin in the blood, 97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction that is actually active and may be excreted.
Drug interactions • Using 2 drugs at the same time may affect each other's fraction unbound. • For example, assume that Drug A and Drug B are both protein- bound drugs. If Drug A is given, it will bind to the plasma proteins in the blood. • If Drug B is also given, it can displace Drug A from the protein, thereby increasing Drug A's fraction unbound. This may increase the effects of Drug A, since only the unbound fraction may exhibit activity.
Effect of Protein Binding on the Apparent Volume of Distribution • The extent of drug protein binding in the plasma or tissue affects V D. Drugs that are highly bound to plasma proteins have a low fraction of free drug • The plasma protein-bound drug does not diffuse easily and is therefore less extensively distributed to tissues
Relationship of Plasma Drug–Protein Binding to Distribution and Elimination • Drugs that are highly bound to plasma protein have reduced overall drug clearance. For a drug that is metabolized mainly by the liver, binding to plasma proteins prevents the drug from entering the hepatocytes, resulting in reduced drug metabolism by the liver.
Determinants of Protein Binding Drug–protein binding is influenced by a number of important factors, including the following: 1. The drug Physicochemical properties of the drug Total concentration of the drug in the body 2. The protein Quantity of protein available for drug–protein binding Quality or physicochemical nature of the protein synthesized 3. The affinity between drug and protein 4. Drug interactions
Relationship between Protein Concentration and Drug Concentration in Drug–Protein Binding • At low drug concentrations, most of the drug may be bound to the protein, whereas at high drug concentrations, the protein- binding sites may become saturated, with a consequent rapid increase in the free drug concentrations