Drug Distribution & Protein Binding

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Understanding the extent and speed of drug distribution is an essential concept in pharmacology. Distribution of drugs from the plasma to tissues primarily occurs through passive diffusion. Drugs may be distributed throughout the volume of plasma water (3L), to the extracellular fluid (15L), or to the intracellular fluid, which represents total body water (40L). Notably, certain areas have looser junctions between capillary epithelial cells, allowing drugs to pass paracellularly.

An essential factor in drug distribution is the degree to which drugs bind to plasma proteins. The bound fraction of a drug cannot permeate membranes or diffuse from plasma to tissues. The unbound portion is represented by the term fu (fraction unbound). Albumin is a primary binding protein for acidic and neutral drugs. Another protein, alpha-1-acid glycoprotein (AGP), binds basic drugs. Pathological conditions that alter plasma protein concentrations can influence the amount of unbound drug. Reversible protein binding will result in an equilibrium between the protein + drug and the protein-drug complex. This binding acts as a drug reservoir, often extending the drug's biological half-life. However, plasma proteins have a finite binding capacity. This characteristic is significant when considering drug interactions. For instance, the warfarin, which binds strongly to albumin, can see a notable increase in exposure if even a small fraction is displaced from its binding sites, leading to potential toxicity. For highly protein-bound drugs, such as warfarin, calcium, and phenytoin, measuring the free or unbound fraction is critical, especially when hypoalbuminemia is present, necessitating corrected calcium and phenytoin levels.

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What factors affect the extent and speed of drug distribution?

The extent and speed of drug distribution are influenced by several factors including the drug's lipid solubility, size, chemical structure, blood flow, the drug's binding to plasma and tissue proteins, as well as the relative permeability of the tissues. The volume of drug distribution is also impacted by the drug's ability to pass through membranes, either paracellularly or through passive diffusion.

How does drug binding to plasma proteins influence drug distribution?

Drugs can bind to plasma proteins such as albumin and alpha-1-acid glycoprotein to varying degrees, which can significantly impact their distribution. The degree to which a drug binds to plasma proteins determines the amount of drug that is free or "unbound" (fu) in the plasma. The unbound fraction of the drug is the therapeutically active portion that can permeate cell membranes and exert a pharmacological effect. Therefore, changes in the concentration of plasma proteins can influence the amount of unbound drug available and thus, its distribution and therapeutic effect.

Why is it important to measure the plasma concentration of a drug?

Measuring the plasma concentration of a drug helps to infer its distribution characteristics, which is key in calculating dosages and observing pharmacokinetic behavior. Furthermore, for highly-protein bound drugs like warfarin or phenytoin, it is important to measure the fraction of drug that is free or unbound in the plasma, as this fraction is responsible for the drug's therapeutic action.

What role does protein binding play in drug interactions?

Significant drug interactions can involve plasma protein binding. For example, warfarin is a drug that is highly protein bound. If another drug is introduced that also binds to the same protein, it can displace warfarin, leading to an increased amount of unbound warfarin in the blood. This can dramatically increase drug exposure and potentially lead to toxicity. Therefore, understanding the intricacies of drug binding to plasma proteins is vital in predicting and preventing adverse drug interactions.

How does plasma protein binding affect the biological half-life of a drug?

Plasma protein binding can act as a reservoir for a drug, which can increase its biological half-life. The bound drug molecules are not readily available for elimination. They must first dissociate from the protein-drug complex before they can be metabolized or excreted. This means that drugs that are highly protein-bound tend to stay in the body longer, thus extending their biological half-life.