Drug Distribution

Introduction to Drug Distribution

Drug distribution refers to the process by which a drug reversibly leaves the site of administration and is dispersed throughout the tissues and fluids of the body. This process is essential for the drug to reach its site of action and exert its pharmacological effects.

• Definition: Distribution is the reversible transfer of a drug between compartments, primarily blood (plasma) and extracellular fluid (ECF).

• Key Compartments: Blood, interstitial fluid, intracellular fluid, fat, and other specialized compartments.

• Mechanism: Driven by circulation of blood and permeability of tissue barriers.

Example: After oral administration, a drug is absorbed into the bloodstream and then distributed to various tissues such as the liver, kidneys, and fat stores.

Body Fluid Compartments

Blood, Interstitial Fluid, and Intracellular Fluid

The human body is composed of several fluid compartments that influence drug distribution.

• Plasma: The liquid component of blood where drugs are initially distributed.

• Interstitial Fluid (IF): The fluid surrounding cells, accounting for about 20% of body water.

• Intracellular Fluid (ICF): The fluid within cells, making up about 45% of body water.

Example: Water composition in a 60 kg individual: total body water is 42 liters (70%), with 27 liters intracellular and 15 liters extracellular (including plasma and interstitial fluid).

Drug Reservoirs

Types of Drug Reservoirs

Body compartments where drugs can accumulate are termed reservoirs. These reservoirs affect drug availability and duration of action.

• Plasma Reservoirs: Albumin, α1-acid glycoprotein

• Tissue/Cellular Reservoirs: Adipose (fat), bone, transcellular (ocular), GI tract

Protein Binding

Mechanisms and Types of Protein Binding

Drugs interact with tissue components, especially proteins, forming complexes that influence pharmacological response.

• Intracellular Binding: Drug-cell protein binding, often elicits pharmacological response (primary receptors).

• Extravascular Binding: Drug-extracellular proteins (e.g., albumin), usually does not elicit pharmacological response (secondary/silent receptors).

Example: Albumin binds large drug molecules, affecting their distribution and free concentration in plasma.

Blood Proteins to Which Drugs Bind

Binding of Drugs to Blood Cells

Red Blood Cells (RBCs) and Drug Binding

More than 40% of blood comprises blood cells, mainly RBCs, which constitute 95% of total blood cells. Drugs can bind to:

• Hemoglobin: Binds drugs like phenytoin and pentobarbital.

• Carbonic anhydrase: Inhibitors like chlorothiazide bind to this enzyme.

• RBC membrane: Basic drugs like imipramine bind to the membrane.

Both hydrophilic and lipophilic drugs can enter RBCs, but lipophilic drugs do so to a greater extent.

Binding of Drugs to Tissues

Tissue Localization and Effects

Binding of drugs to tissues is a vital process that enhances the apparent volume of distribution and can prolong the duration of action due to increased half-life.

Fats as a Reservoir

Role of Adipose Tissue in Drug Distribution

Fat is a large, non-polar compartment with low blood supply (less than 2% of cardiac output), so drugs are delivered to fat slowly. Distribution varies with body composition.

• Obese individuals: Store large amounts of fat-soluble drugs.

• Thin individuals: Store relatively little fat-soluble drugs.

• Age: Older people may store more fat-soluble drugs due to increased body fat.

• Example: Highly lipid-soluble drug barbiturate thiopental.

Physiological Barriers to Drug Distribution

Types of Barriers

• Simple Capillary Endothelial Barrier: Capillaries allow drugs with molecular size less than 600 Daltons to diffuse; larger complexes are restricted.

• Simple Cell Membrane Barrier: Drug entry into cells is limited by membrane permeability, similar to the lipoidal barrier in GI absorption.

• Blood-Brain Barrier (BBB): Brain capillaries have tight junctions, blocking intercellular passage. Only drugs with high oil/water partition coefficients can diffuse passively.

• Placental Barrier: Drugs with molecular weight less than 1000 Daltons and moderate to high lipid solubility cross by diffusion; less effective than BBB.

Bioavailability

Definition and Importance

Bioavailability is the measure of the rate and extent to which the active drug ingredient is absorbed and becomes available at the site of action.

• Definition: Bioavailability (%F) is the amount of drug that reaches the systemic circulation after absorption and first-pass clearance.

• Fraction of unchanged drug: The proportion of administered drug reaching systemic circulation unchanged.

Example: Oral drugs may have lower bioavailability than intravenous drugs due to first-pass metabolism.

Absolute vs. Relative Bioavailability

• Absolute Bioavailability: Systemic availability after extravascular administration compared to IV dosing.

• Relative (Apparent) Bioavailability: Availability of drug from a product compared to a recognized standard or dosage form.

Volume of Distribution (Vd)

Definition and Calculation

Volume of distribution (Vd) is a pharmacokinetic parameter that relates the total amount of drug in the body to its concentration in plasma.

• Definition: The volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood.

• Formula:

• Vd can exceed physical body volume: Example: Chloroquine Vd = 15,000 L.

Vd of Some Drugs

• Factors affecting Vd: Lipid solubility, plasma protein binding (PPB), tissue protein affinity, fat/lean body mass, disease states (CHF, uremia, cirrhosis).

Summary Table: Key Concepts

Additional info: These principles are foundational in pharmacokinetics and are essential for understanding how drugs behave in the body, influencing dosing, efficacy, and safety.