Pharmacokinetics (distribution)

One-Compartment Model

• The concentration-time profile (or course) of a drug following an intravenous bolus injection can be represented by a one-compartment model.
• Areas under the concentration-time curve (AUC) are used to calculate various pharmacokinetic parameters that reflect how a drug is absorbed, distributed, metabolized, and excreted.

Two-Compartment Model

• Some drugs are better described with a two-compartment model. This model divides the body into a central compartment (blood) and a peripheral compartment (tissues like fat, muscle, liver, etc.)
• The central compartment is where the drug is distributed rapidly, while the peripheral compartment represents areas with slower distribution.

Multi-Compartment Model

• When more than two compartments are necessary to accurately describe the pharmacokinetic profile of a drug.
• Less commonly used.

Drug Distribution

• The extent and rate of drug distribution are impacted by several factors:
  • The physicochemical nature of the drug (e.g., its solubility, size, ionization)
  • Organ perfusion rate (blood flow to organs)
  • Permeability of tissue membranes (how easily the drug can cross cell membranes)
  • Plasma protein binding (the extent to which the drug binds to proteins in the blood)
  • Tissue binding (the extent to which the drug binds to proteins and other molecules in tissues)

Drug Distribution Principles

• Only the free (unbound) form of the drug can permeate across biological membranes.

Protein Binding

• Many drugs bind to plasma proteins:
  • Acidic drugs bind to albumin (e.g., salicylates)
  • Basic drugs bind to α1-acid glycoprotein (e.g., propranolol)
• Protein binding is typically reversible and saturable.
  • At high drug concentrations, protein binding may become saturated.
• For most drugs, the therapeutic range is well below the saturation point, so the percent bound remains relatively constant.

Tissue Binding

• Many drugs exhibit higher concentrations in tissues compared to extracellular fluids and blood.
• For example, quinacrine (an antimalarial) can be found in much higher concentrations in the liver than in the blood.
• Tissue binding can involve cellular components like proteins, phospholipids, and nuclear proteins.
• Tissue binding is typically reversible and can act as a drug reservoir.

Distribution Principles

• Drugs with high plasma protein binding often have a small volume of distribution.
• Drugs with high tissue binding usually have a large volume of distribution.

Elimination

• Elimination involves removing drugs from the body.
• Two primary processes are responsible for elimination:
  • Metabolism: primarily carried out by the liver
  • Excretion: primarily performed by the kidneys, but other routes like bile are also possible

Important PK Parameters

• Volume of distribution (Vd)
• Clearance (CL)
• Half-life (t1/2)

Volume of Distribution (Vd)

• Vd is a calculated volume that relates the amount of drug in the body to the concentration in blood or plasma.
• It's an apparent volume, not a real physiological volume.
• The Vd can exceed any physical volume in the body because it represents the hypothetical volume needed to contain the drug homogeneously at the blood or plasma concentration.

Volume of Distribution Examples

• Digoxin: Vd = 500 L
• Chloroquine: Vd = 13,000 L
• Gentamicin: Vd = 18 L
• Drugs with large Vd values are not distributed evenly throughout the body.

Clearance (CL)

• Clearance is a measure of the body's efficiency at eliminating a drug.
• Clearance is the most important factor determining drug concentrations.
• It reflects the rate of drug elimination in relation to the drug concentration.
• Clearance is additive, meaning various organs can contribute to overall clearance.

Factors Affecting Clearance

• Dose:
  • Some drugs, like ethanol, exhibit capacity-limited elimination, meaning clearance may be slowed at high doses.
• Organ blood flow:
  • High-extraction drugs (e.g., lidocaine) are rapidly cleared by organs with high blood flow like the liver.
• Intrinsic function of the liver or kidneys:
  • Reduced organ function can lower clearance.
• The unbound fraction of drug:
  • The free (unbound) portion of the drug is available for clearance.
  • High protein binding can decrease clearance.

Protein Binding and Clearance

• High protein binding can decrease clearance by reducing the amount of free drug available for metabolism and excretion.

Half-life (t1/2)

• Half-life (t1/2) is the time required for the amount of drug in the body to decrease by 50% during elimination or during a constant IV infusion.
• Half-life is useful for determining how long it takes for drug concentrations to reach 50% of their initial value or to reach 50% of steady-state concentration.

Half-life (t1/2) and Steady State

• For repeated oral administration, steady-state concentration (Css) is typically achieved after approximately four half-lives.

This quiz covers the various compartment models used in pharmacokinetics, including the one-compartment, two-compartment, and multi-compartment models. You'll explore how these models help in understanding the distribution of drugs within the body. Test your knowledge of drug absorption, distribution, metabolism, and excretion through this detailed overview.